Octahydro fused azadecalin glucocorticoid receptor modulators

ABSTRACT

The present invention provides octahydro fused azadecalin compounds and methods of using the compounds as glucocorticoid receptor modulators.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Nos.61/985,035, filed Apr. 28, 2014, and 61/908,333, filed Nov. 25, 2013,each of which is incorporated in its entirety herein for all purposes.

BACKGROUND OF THE INVENTION

In most species, including man, the physiological glucocorticoid iscortisol (hydrocortisone). Glucocorticoids are secreted in response toACTH (corticotropin), which shows both circadian rhythm variation andelevations in response to stress and food. Cortisol levels areresponsive within minutes to many physical and psychological stresses,including trauma, surgery, exercise, anxiety and depression. Cortisol isa steroid and acts by binding to an intracellular, glucocorticoidreceptor (GR). In man, glucocorticoid receptors are present in twoforms: a ligand-binding GR-alpha of 777 amino acids; and, a GR-betaisoform which lacks the 50 carboxy terminal residues. Since theseinclude the ligand binding domain, GR-beta is unable to bind the naturalligand, and is constitutively localized in the nucleus. The GR is alsoknown as the GR-II receptor.

The biologic effects of cortisol, including those caused byhypercortisolemia, can be modulated at the GR level using receptormodulators, such as agonists, partial agonists and antagonists. Severaldifferent classes of agents are able to block the physiologic effects ofGR-agonist binding. These antagonists include compositions which, bybinding to GR, block the ability of an agonist to effectively bind toand/or activate the GR. One such known GR antagonist, mifepristone, hasbeen found to be an effective anti-glucocorticoid agent in humans(Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone bindsto the GR with high affinity, with a dissociation constant (K_(d)) of10⁻⁹ M (Cadepond (1997) Annu. Rev. Med. 48:129). What is needed in theart are new compositions and methods for modulating GR receptors.Surprisingly, the present invention meets these and other needs.

BRIEF SUMMARY OF THE INVENTION

The present invention provides many fused azadecalin compounds. In someembodiments, the present invention provides compounds having theformula:

wherein R¹ of formula I is a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 4 heteroatoms, which can each independently be N,O, or S, optionally substituted with 1-4 groups, which can eachindependently be R^(1a). Each R^(1a) of formula I can independently behydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, N-oxide, or C₃₋₈ cycloalkyl. Ring J of formula I can be anaryl ring or a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms, which can each independently be N, O, or S. Each R²of formula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN,—OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b),—SR^(2a), —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, or C₃₋₈heterocycloalkyl having from 1 to 3 heteroatoms wherein each canindependently be N, O, or S. Alternatively, two R² groups on adjacentring atoms are combined to form a heterocycloalkyl ring having from 5 to6 ring members and from 1 to 3 heteroatoms, which can each independentlybe N, O, or S, wherein the heterocycloalkyl ring is optionallysubstituted with from 1 to 3 R^(2c) groups. R^(2a), R^(2b) and R^(2c) offormula I can each independently be hydrogen or C₁₋₆ alkyl. Each R^(3′)of formula I can independently be a halogen. Subscript n of formula Ican be an integer from 0 to 3. The compounds of formula I can also bethe salts and isomers thereof.

In some embodiments, the present invention provides a pharmaceuticalcomposition including a compound of the present invention and apharmaceutically acceptable excipient.

In some embodiments, the present invention provides a method ofmodulating a glucocorticoid receptor including contacting aglucocorticoid receptor with a compound of the present invention,thereby modulating the glucocorticoid receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 2, 3 and 4 show various synthetic schemes for making thecompounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION I. General

The present invention provides compounds capable of modulating aglucocorticoid receptor (GR) and thereby providing beneficialtherapeutic effects. The compounds include octahydro fused azadecalins.The present invention also provides methods of treating diseases anddisorders by modulating a GR receptor with the compounds of the presentinvention.

II. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec_butyl, tert_butyl,pentyl, isopentyl, hexyl, etc.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Halogen” refers to fluorine, chlorine, bromine and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆. For example, haloalkyl includes trifluoromethyl, fluoromethyl,etc. In some instances, the term “perfluoro” can be used to define acompound or radical where all the hydrogens are replaced with fluorine.For example, perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2]bicyclooctane,decahydronaphthalene and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O and S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8,6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, having a methylene linking group. Some arylgroups have from 6 to 12 ring members, such as phenyl, naphthyl orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O or S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, N-oxide, —S(O)— and —S(O)₂—. Heteroaryl groups can include anynumber of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Anysuitable number of heteroatoms can be included in the heteroaryl groups,such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring membersand from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.The heteroaryl group can include groups such as pyrrole, pyridine,imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroarylgroups can also be fused to aromatic ring systems, such as a phenylring, to form members including, but not limited to, benzopyrroles suchas indole and isoindole, benzopyridines such as quinoline andisoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3-and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazoleincludes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine,1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-,5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiopheneincludes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazoleincludes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindoleincludes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline,isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2-and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline,benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes2- and 3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroatoms” refers to O, S or N.

“Salt” refers to acid or base salts of the compounds used in the methodsof the present invention. Illustrative examples of pharmaceuticallyacceptable salts are mineral acid (hydrochloric acid, hydrobromic acid,phosphoric acid, and the like) salts, organic acid (acetic acid,propionic acid, glutamic acid, citric acid and the like) salts,quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.It is understood that the pharmaceutically acceptable salts arenon-toxic. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors and colors, and the like. One of skill in the art will recognizethat other pharmaceutical excipients are useful in the presentinvention.

“Modulating a glucocorticoid receptor” refers to methods for adjustingthe response of a glucocorticoid receptor towards glucocorticoids,glucocorticoid antagonists, agonists, and partial agonists. The methodsinclude contacting a glucocorticoid receptor with an effective amount ofeither an antagonist, an agonist, or a partial agonist and detecting achange in GR activity.

“GR modulator” refers to compounds that agonize and/or antagonize theglucocorticoid receptor and are defined as compounds of Formula I below.

“Glucocorticoid receptor” (“GR”) refers to a family of intracellularreceptors which specifically bind to cortisol and/or cortisol analogs(e.g. dexamethasone). The glucocorticoid receptor is also referred to asthe cortisol receptor. The term includes isoforms of GR, recombinant GRand mutated GR.

“Glucocorticoid receptor antagonist” refers to any composition orcompound which partially or completely inhibits (antagonizes) thebinding of a glucocorticoid receptor (GR) agonist, such as cortisol, orcortisol analogs, synthetic or natural, to a GR. A “specificglucocorticoid receptor antagonist” refers to any composition orcompound which inhibits any biological response associated with thebinding of a GR to an agonist. By “specific,” the drug to preferentiallybind to the GR rather than other nuclear receptors, such asmineralocorticoid receptor (MR) or progesterone receptor (PR).

“Contacting” refers to the process of bringing into contact at least twodistinct species such that they can react with one another or interactsuch that one has an effect on the other.

“Treat”, “treating” and “treatment” refer to any indicia of success inthe treatment or amelioration of an injury, pathology or condition,including any objective or subjective parameter such as abatement;remission; diminishing of symptoms or making the injury, pathology orcondition more tolerable to the patient; slowing in the rate ofdegeneration or decline; making the final point of degeneration lessdebilitating; improving a patient's physical or mental well-being. Thetreatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals and othernon-mammalian animals.

“Disorder” or “condition” refer to a state of being or health status ofa patient or subject capable of being treated with the glucocorticoidreceptor modulators of the present invention. Examples of disorders orconditions include, but are not limited to, obesity, hypertension,depression, anxiety, and Cushing's Syndrome.

“Antagonizing” refers to blocking the binding of an agonist at areceptor molecule or to inhibiting the signal produced by areceptor-agonist. A receptor antagonist blocks or dampensagonist-mediated responses.

“Therapeutically effective amount” refers to an amount of a conjugatedfunctional agent or of a pharmaceutical composition useful for treatingor ameliorating an identified disease or condition, or for exhibiting adetectable therapeutic or inhibitory effect. The effect can be detectedby any assay method known in the art.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, or physiological conditions.

III. Compounds

The present invention provides many fused azadecalin compounds. In someembodiments, the present invention provides compounds having theformula:

wherein R¹ of formula I is a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 4 heteroatoms, which can each independently be N,O, or S, optionally substituted with 1-4 groups, which can eachindependently be R^(1a). Each R^(1a) of formula I can independently behydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, N-oxide, or C₃₋₈ cycloalkyl. Ring J of formula I can be anaryl ring or a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms, which can each independently be N, O, or S. Each R²of formula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN,—OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a), —C(O)NR^(2a)R^(2b),—SR^(2a), —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, or C₃₋₈heterocycloalkyl having from 1 to 3 heteroatoms wherein each canindependently be N, O, or S. Alternatively, two R² groups on adjacentring atoms are combined to form a heterocycloalkyl ring having from 5 to6 ring members and from 1 to 3 heteroatoms, which can each independentlybe N, O, or S, wherein the heterocycloalkyl ring is optionallysubstituted with from 1 to 3 R^(2c) groups. R^(2a), R^(2b) and R^(2c) offormula I can each independently be hydrogen or C₁₋₆ alkyl. Each R^(3a)of formula I can independently be a halogen. Subscript n of formula Ican be an integer from 0 to 3. The compounds of formula I can also bethe salts and isomers thereof.

In some embodiments, wherein R¹ of formula I can be a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms which caneach independently be N, O, or S, optionally substituted with 1-3 groupseach independently selected from R^(1a). Each R^(1a) of formula I can behydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or C₃₋₈ cycloalkyl. Ring J of formula I can be an aryl ringor a heteroaryl ring having from 5 to 6 ring members and from 1 to 3heteroatoms which can each independently be N, O, or S. Each R² offormula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, CN, —NR^(2a)R^(2b), C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkylhaving from 1 to 3 heteroatoms which can each independently be N, O, orS. N, O, or S, wherein the heterocycloalkyl ring is optionallysubstituted with from 1 to 3 R^(2c) groups. R^(2a), R^(2b) and R^(2c) offormula I can each independently be hydrogen or C₁₋₆ alkyl. Each R^(3a)can independently be halogen. Subscript n of formula I can be an integerfrom 0 to 3. The compounds of formula I can also be the salts andisomers thereof.

In some embodiments, R¹ can be a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 3 heteroatoms which each can independently be N,O, or S, optionally substituted with 1-2 groups which can eachindependently be R^(1a). Each R^(1a) can independently be hydrogen, C₁₋₆alkyl, halogen, or C₁₋₆ haloalkyl. Ring J can be an aryl ring or aheteroaryl ring having from 5 to 6 ring members and from 1 to 3heteroatoms, which can independently be N or S. Each R² of formula I canindependently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl or —CN.R^(3a) can be F. Subscript n can be an integer from 0 to 1.

In some embodiments, R¹ can be a heteroaryl ring having from 5 to 6 ringmembers and from 1 to 3 heteroatoms which can each independently be N orS, optionally substituted with 1-2 groups which can each independentlybe R^(1a). Each R^(1a) can independently be hydrogen, C₁₋₆ alkyl, orC₁₋₆ haloalkyl. Ring J can be phenyl, pyridine, pyrazole, or triazole.Each R² can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl or —CN. R^(1a) can be F.

In some embodiments, R¹ can be pyridine or thiazole. Ring J can bephenyl, pyridine, pyrazole, or triazole. Each R² can independently behydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl or —CN. R^(3′) can be F.In some embodiments, R¹ can be 2-thiazole, 4-thiazole, 5-thiazole,2-pyridine, 3-pyridine, or 4-pyridine. In some embodiments, R¹ can be2-pyridine; 2-thiazole; or 4-thiazole. In some embodiments, R¹ can bepyridine. In some embodiments, R¹ can be triazole. In some embodiments,R^(1a) can independently be hydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl. Insome embodiments, R^(1a) can independently be hydrogen, methyl, ortrifluoromethyl.

In some embodiments, ring J can be phenyl, pyridine, pyrazole, ortriazole. In some embodiments, ring J can be phenyl, 2-pyridine,3-pyridine, 4-pyridine, 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole,1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, or1,2,4-triazol-5-yl. In some embodiments, R² can independently behydrogen, methyl, ethyl, propyl, isopropyl, F, Cl, or —CF₃.

The compounds of the present invention include at least one stereogeniccenter at the bridgehead carbon. Accordingly, the compounds can includea mixture of isomers, including enantiomers in a racemic mixture, or inenantiomerically pure mixtures that are substantially the R- orS-isomer. The compounds can also adopt a cis- or trans-conformationacross the bridgehead carbons (carbons 4a and 8a) of the4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline portion ofthe compounds. In some embodiments, the compounds of formula I can havethe following structure:

Any suitable heteroaryl can be used for R¹ in the compounds of thepresent invention, as defined in the definitions above. In someembodiments, the heteroaryl of R¹ can have from 5 to 6 ring members andfrom 1 to 4 heteroatoms which can each independently be N, O or S,optionally substituted with 1-4 groups which can each independently beR^(1a). In some embodiments, the heteroaryl of R¹ can have from 5 to 6ring members and from 1 to 3 heteroatoms which can each independently beN, O or S, optionally substituted with 1-4 groups which can eachindependently be R^(1a). In some embodiments, the heteroaryl of R¹ canhave from 5 to 6 ring members and from 1 to 2 heteroatoms which can eachindependently be N, O or S, optionally substituted with 1-4 groups whichcan each independently be R^(1a). In some embodiments, the heteroaryl ofR¹ can have from 5 to 6 ring members and from 1 to 2 heteroatoms whichcan each independently be N or S, optionally substituted with 1-4 groupswhich can each independently be R^(1a).

In some embodiments, the heteroaryl of R¹ can be pyrrole, pyrazole,imidazole, triazole, tetrazole, furan, oxazole, isoxazole, oxadiazole,thiophene, thiazole, isothiazole, thiadiazole, pyridine, pyrazine,pyrimidine, or pyridazine. In some embodiments, the heteroaryl of R¹ canbe 2-pyrrole, 3-pyrrole, 1-pyrazole, 3-pyrazole, 4-pyrazole, 5-pyrazole,2-imidazole, 4-imidazole, 5-imidazole, 1,2,3-triazol-4-yl,1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1,2,3,4-tetrazol-1-yl, 1,2,3,4,tetrazol-5-yl, 2-furan, 3-furan,2-oxazole, 4-oxazole, 5-oxazole, 3-isoxazole, 4-isooxazole,5-isooxazole, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene,2-thiazole, 4-thiazole, 5-thiazole, 3-isothiazole, 4-isothiazole,5-isothiazole, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl,1,3,4-thiadiazol-2-yl, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine,2-pyrimidine, 4-pyrimidine, 5-pyrimidine, 6-pyrimidine, 3-pyridazine,4-pyridazine, 5-pyridazine, or 6-pyridazine. In some embodiments, theheteroaryl of R¹ can be pyrazole, imidazole, triazole, furan, oxazole,oxadiazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine. Insome embodiments, the heteroaryl of R¹ can be imidazole, furan, oxazole,oxadiazole, thiophene, thiazole, or pyridine.

In some embodiments, the heteroaryl of R¹ can be 1-pyrazole, 3-pyrazole,4-pyrazole, 5-pyrazole, 2-imidazole, 4-imidazole, 5-imidazole,1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, 2-furan, 3-furan, 2-oxazole, 4-oxazole, 5-oxazole,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl,1,3,4-oxadiazol-2-yl, 2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole,5-thiazole, 2-pyridine, 3-pyridine, 4-pyridine, pyrazine, 2-pyrimidine,4-pyrimidine, 5-pyrimidine, or 6-pyrimidine. In some embodiments, theheteroaryl of R¹ can be 3-pyrazole, 4-pyrazole, 2-imidazole,1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole, 1,3,4-oxadiazol-2-yl,2-thiophene, 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine, 3-pyridine,4-pyridine, pyrazine, or 2-pyrimidine. In some embodiments, theheteroaryl of R¹ can be 2-imidazole, 4-imidazole, 5-imidazole, 2-furan,3-furan, 2-oxazole, 4-oxazole, 5-oxazole, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl,2-thiophene, 3-thiophene, 2-thiazole, 4-thiazole, 5-thiazole,2-pyridine, 3-pyridine, or 4-pyridine.

In some embodiments, the heteroaryl of R¹ can be pyridine or thiazole.In some embodiments, the heteroaryl of R¹ can be 2-thiazole, 4-thiazole,5-thiazole, 2-pyridine, 3-pyridine, or 4-pyridine. In some embodiments,the heteroaryl of R¹ can be 2-thiazole, 4-thiazole or 2-pyridine. Insome embodiments, the heteroaryl of R¹ can be pyridine. In someembodiments, the heteroaryl of R¹ can be thiazole.

In some embodiments, the heteroaryl of R¹ can be optionally substitutedwith 1-4 groups which can each independently be R^(1a). In someembodiments, each R^(1a) can independently be hydrogen, C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —CN, N-oxide,C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl. In some embodiments, eachR^(1a) can independently be hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy or C₃₋₈ heterocycloalkyl. In some embodiments, each R^(i)a canindependently be hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₁₋₆ alkoxy.In some embodiments, each R^(1a) can independently be hydrogen, C₁₋₆alkyl, or C₁₋₆ haloalkyl. In some embodiments, each R^(1a) canindependently be hydrogen or C₁₋₆ alkyl. The alkyl of R^(1a) can be anysuitable alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, andhexyl, among others. In some embodiments, each R^(1a) can independentlybe hydrogen, methyl, ethyl, trifluoromethyl, methoxy, or pyrrolidinyl.In some embodiments, each R^(1a) can independently be hydrogen, methyl,or trifluoromethyl. In some embodiments, each R^(1a) can independentlybe hydrogen or methyl.

In some embodiments, the heteroaryl of R¹ can be 3-pyrazole, 4-pyrazole,2-imidazole, 1,2,4-triazol-5-yl, 2-furan, 2-oxazole, 4-oxazole,1,3,4-oxadiazol-2-yl, 2-thiophene, 2-thiazole, 4-thiazole, 5-thiazole,2-pyridine, 3-pyridine, 4-pyridine, pyrazine, or 2-pyrimidine, and RingJ can be 2-pyridine, 3-pyridine, 4-pyridine, imidazol-2-yl,imidazol-4-yl, imidazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, or isoxazol-4-yl.

Ring J of formula I can be any suitable ring. In some embodiments, ringJ of formula I can be a cycloalkyl ring, a heterocycloalkyl ring, anaryl ring or a heteroaryl ring, wherein the heterocycloalkyl andheteroaryl rings can have from 5 to 6 ring members and from 1 to 4heteroatoms which can each independently be N, O or S. In someembodiments, ring J can be heterocycloalkyl, aryl or heteroaryl.Suitable heterocycloalkyl groups include those defined in thedefinitions above. In some embodiments, the heterocycloalkyl cantetrahydrofuran. Suitable aryl groups for ring J include those definedin the definitions above. Representative aryl groups include phenyl andnaphthyl. In some embodiments, the aryl group of ring J can be phenyl.Suitable heteroaryl groups for ring J include those defined in thedefinitions above. Representative heteroaryl groups include pyrrole,pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine,pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers),thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. In someembodiments, the heteroaryl can be pyridyl or thiophene. In someembodiments, ring J can be aryl or heteroaryl. In some embodiments, ringJ can be phenyl, pyridine, imidazole, pyrazole, triazole, tetrazole,thiadiazole, isothiazole, or isoxazole. In some embodiments, ring J canbe phenyl, pyridine, pyrazole or triazole. In some embodiments, ring Jcan be phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 1-pyrazole,3-pyrazole, 4-pyrazole, 5-pyrazole, 1,2,3-triazol-4-yl,1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl, and 1,2,4-triazol-5-yl. In someembodiments, ring J can be phenyl. In some embodiments, ring J can bepyridine. In some embodiments, ring J can be pyrazole. In someembodiments, ring J can be triazole.

Ring J of formula I can be substituted with any suitable number of R²groups. Each R² of formula I can independently be hydrogen, C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆alkoxy, —CN, —OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a),—C(O)NR^(2a)R^(2b), —SR^(2a), —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈cycloalkyl, or C₃₋₈ heterocycloalkyl, wherein the heterocycloalkylgroups are optionally substituted with 1-4 R^(2c) groups. In someembodiments, each R² of formula I can independently be hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, R^(2b), —C(O)OR^(2a), —S(O)₂R^(2a), C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN, —NR^(2a), C₃₋₈cycloalkyl, or C₃₋₈ heterocycloalkyl, wherein the heterocycloalkyl grouphas 5-6 ring members and 1 to 2 heteroatoms. In some embodiments, eachR² of formula I can independently be hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, —CN,—NR^(2a)R^(2b), —S(O)₂R^(2a), C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl,wherein the heterocycloalkyl group has 5-6 ring members and 1 to 2heteroatoms. Each R² of formula I can independently be hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —CN,—NR^(2a)R^(2b), C₃₋₈ cycloalkyl, or C₃₋₈ heterocycloalkyl, wherein theheterocycloalkyl groups are optionally substituted with 1-4 R^(2c)groups. In some embodiments, each R² can independently be hydrogen,halogen, C₁₋₆ haloalkyl, —CN, or heterocycloalkyl having 5-6 ringmembers and 1 to 2 heteroatoms wherein at least one heteroatom is N.Heterocycloalkyl groups having 5-6 ring members and 1 to 2 heteroatomswith at least one nitrogen include, but are not limited to, pyrrolidine,piperidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and1,4-isomers), oxazolidine, isoxalidine, thiazolidine, isothiazolidine,morpholine, or thiomorpholine. In some embodiments, each R² canindependently be hydrogen, methyl, ethyl, propyl, isopropyl, F, Cl,—CF₃, CH₂OMe, OMe, OCHF₂, —CN, —NMe₂, —C(O)OH, —C(O)NMe₂, —S(O)₂Me,pyrrolidine, piperidine or morpholine. In some embodiments, each R² canindependently be hydrogen, methyl, ethyl, F, Cl, —CF₃, OMe, OCHF₂, —CN,—NMe₂, —S(O)₂Me, pyrrolidine, piperidine or morpholine. In someembodiments, each R² can independently be hydrogen, methyl, ethyl,n-propyl, isopropyl, F, Cl, and —CF₃. In some embodiments, R² can be—CF₃. Ring J can be substituted with 1, 2, 3 or 4 R² groups. In someembodiments, ring J is substituted with 1 R² group.

Alternatively, two R² groups on adjacent atoms of Ring J can be combinedto form a heterocycloalkyl ring having from 5 to 6 ring members and from1 to 3 heteroatoms that can each be N, O or S, wherein theheterocycloalkyl ring is optionally substituted with from 1 to 3 R^(2c)groups. When two R² groups are combined, any suitable heterocycloalkylgroups can be formed. In some embodiments, the heterocycloalkyl formedby the combination of two R² groups can have 6 ring members and from 1to 2 heteroatoms that can each be N, O or S. In some embodiments, theheterocycloalkyl formed by the combination of two R² groups can have 6ring members and from 1 to 2 heteroatoms that can each be N or O. Insome embodiments, the heterocycloalkyl formed by the combination of twoR² groups can have 6 ring members and 2 heteroatoms that can each be Nor O. In some embodiments, the heterocycloalkyl formed by thecombination of two R² groups can be morpholine. When ring J is pyridineand the heterocycloalkyl formed by the combination of two R² groups, thecombination can be any suitable pyrido-oxazine such as3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl. And when the two R² groupsare combined to form a heterocycloalkyl, the heterocycloalkyl can besubstituted with from 1 to 3 R^(2c) groups such as H or Me.

Several R² groups can be further substituted with one or more of R^(2a)and R^(2b). R^(2a) and R^(2b) can each independently be hydrogen or C₁₋₆alkyl.

Each R^(3a) can be any halogen. In some embodiments, each R^(3a) groupcan independently be F, I, Cl, or Br. In some embodiments, R^(3a) can beF. The R^(3a) group can be present at any position on the phenyl ring toform a 2-, 3- or 4-substituted ring. In some embodiments, the phenylring is substituted at the 4-position.

Subscript n of formula I can be an integer from 0 to 3. In someembodiments, subscript n can be 0, 1, 2, or 3. In some embodiments,subscript n can be 0 or 1. In some embodiments, subscript n can be 0. Insome embodiments, subscript n can be 1.

When R^(3a) of formula I is 4-fluoro, the compounds of the presentinvention can have the following structure:

In some embodiments, the compound of formula I can be:

-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8    aS)-6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   3-(((4aR,8aS)-1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile,-   ((4aR,8aS)-6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-6-((2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,-   ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,    or-   ((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone.

The compounds of the present invention can also be the salts and isomersthereof. In some embodiments, the compounds of the present inventioninclude the salt forms thereof Examples of applicable salt forms includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures),succinates, benzoates and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in art.When compounds of the present invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples of acceptableacid addition salts include those derived from inorganic acids likehydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from organic acids like acetic, propionic,isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric,lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science,1977, 66, 1-19). Certain specific compounds of the present inventioncontain functionalities that allow the compounds to be converted intobase addition salts. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the enantiomers, racemates,diastereomers, tautomers, geometric isomers, stereoisometric forms thatmay be defined, in terms of absolute stereochemistry, as (R)- or (S)-or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques.

Isomers include compounds having the same number and kind of atoms, andhence the same molecular weight, but differing in respect to thestructural arrangement or configuration of the atoms.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention. Tautomerrefers to one of two or more structural isomers which exist inequilibrium and which are readily converted from one isomeric form toanother.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, the compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds of thepresent invention may be radiolabeled with radioactive isotopes, such asfor example deuterium (²H), tritium (³H), iodine-125 (¹²⁵I), carbon-13(¹³C), or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Compounds of the present invention can be prepared as shown in FIG. 1.Starting materials can be obtained from commercial sources, by employingknown synthetic methods, and by employing methods described in U.S. Pat.No. 7,928,237, incorporated herein by reference. Esters I are convertedto ketones IV by reaction with an appropriate organometallic reagentsuch as a Grignard reagent, an organolithium reagent, an organoboronreagent, an organocerium reagent or an organozinc reagent in a solventsuch as ether or tetrahydrofuran, or a similar aprotic solvent.Preferably, the reaction is carried out by using an aryl lithium reagentin a solvent such as ether or tetrahydrofuran. It may be advantageous tocarry out the reaction at reduced temperature. Ketones of formula IV arealso prepared by reaction of an aldehyde of formula II with anappropriate organometallic reagent followed by oxidation of theresultant alcohols of formula III with a suitable oxidizing agent suchas the Dess-Martin periodinane reagent in an inert solvent such asdichloromethane. The tert-butoxycarbonyl protecting group is removedfrom IV by treatment with an acid, such as HCl, HBr, trifluoroaceticacid, p-toluenesulfonic acid or methanesulfonic acid, preferably HCl ortrifluoroacetic acid, optionally in a solvent such as dioxane,dichloromethane, ethanol or tetrahydrofuran, either under anhydrous oraqueous conditions. Preferably, the reaction is carried out using eitherHCl in dioxane, or trifluoroacetic acid in dichloromethane. Amines V areconverted to the compounds of formula (1) by treatment with anappropriate substituted sulfonyl halide, such as the sulfonyl chlorideVI, in an inert solvent such as dichloromethane, toluene ortetrahydrofuran, preferably dichloromethane, in the presence of a basesuch as N,N-di-isopropylethylamine or triethylamine. It may beconvenient to carry out the sulfonylation reaction in situ, withoutisolation of the amine V. Compounds of formula (1) can also be preparedfrom amines of formula V in a two-step sequence beginning with reactionof amines V with a halo-substituted sulfonyl chloride, VII, to afford ahalo-substituted sulfonamide derivative exemplified by VIII (in which Xrepresents a halogen). The halogen substituent X can be converted in asubstituent R² by any standard method known to those skilled in the art.

Alternatively, compounds of formula (1) are prepared as shown FIG. 2.The tert-butoxycarbonyl protecting group is removed from I by treatmentwith an acid, such as HCl, HBr, trifluoroacetic acid, p-toluenesulfonicacid or methanesulfonic acid, preferably HCl or trifluoroacetic acid,optionally in a solvent such as dioxane, dichloromethane, ethanol ortetrahydrofuran, either under anhydrous or aqueous conditions.Preferably, the reaction is carried out using either HCl in dioxane, ortrifluoroacetic acid in dichloromethane. Amines IX are converted to thesulfonamides of formula X as described for the conversion of amines offormula V into sulfonamides of formula (1). The ester group in compoundsof formula X is converted to an aldehyde of formula XI by using areducing agent such as DIBAL-H, LiAlH₄ or RED-AL, preferably DIBAL-H inan inert solvent such as dichloromethane, tetrahydrofuran, benzene ortoluene, preferably dichloromethane. It may be convenient to convert Xinto XI using a two-step process involving reduction of the ester to analcohol and subsequent oxidation of the alcohol to an aldehyde offormula XI. The oxidation can be carried out using any suitableprocedure, such as the Swern reaction, or an oxidizing reagent such asthe Dess-Martin periodinane reagent in a suitable solvent, such asdichloromethane. Aldehydes of formula XI are converted into alcohols offormula XII using a suitable organometallic reagent, such as a Grignardreagent, an organolithium reagent, an organoboron reagent, anorganocerium reagent or an organozinc reagent. Alcohols of formula XIIare converted into ketones of formula (1) by oxidation. Suitableoxidation conditions include the Swern reaction and the use of theDess-Martin periodinane reagent. Alternatively, esters of formula X areconverted directly to ketones of formula (1) using an appropriateorganometallic reagent, preferably an aryl lithium reagent in a suitablesolvent, such as ether or tetrahydrofuran.

Compounds of formula I in which J represents a triazole and R²represents alkyl require the synthesis of the appropriate triazolesulfonyl chloride. The triazole sulfonyl chlorides employed in thecurrent invention may be prepared by any suitable method known to thoseskilled in the art, such as the method depicted in FIG. 3. In FIG. 3,alk represents an alkyl group. The commercially available triazole thiolXIII is converted into a suitably protected thiol, such as thebenzylthio triazole XIV, using any suitable conditions known to thoseskilled in the art. Preferably, thiol XIII is treated with benzylbromide in a suitable solvent, such as ethanol. Alkylation of aprotected thiol, such as benzyl thiol XIV provides a mixture of threeregioisomeric alkyl pyrazoles XVa, XVb and XVc. The exact ratio of theproducts depends on the conditions used for the alkylation reaction. Forexample, the use of an appropriate alkyl iodide in N,N-dimethylformamidein the presence of potassium carbonate provides triazole XVa as themajor product. The regiochemistry of the alkylated triazoles isdetermined using any suitable method known to those skilled in the art.For example, regiochemistry may be assigned by comparison withinformation in the scientific literature, by undertaking NOEexperiments, by chemical manipulation to provide compounds of knownstructure, or by comparison with samples made by an alternative,unambiguous synthetic route. For example, the synthetic route depictedin FIG. 4 specifically provides triazole sulfides of formula XVc. InFIG. 4, alk represents an alkyl group.

Triazoles of formula XV are converted into sulfonyl chlorides of formulaXVI using any appropriate method known to those skilled in the art. Forexample, oxidative cleavage of the thiobenzyl group using a suitableoxidizing agent may be employed. The use of N-chlorosuccinimide orchlorine gas, in a suitable solvent such as acetic acid, providessulfonyl chlorides of formula XVI.

IV. Pharmaceutical Compositions

In some embodiments, the present invention provides a pharmaceuticalcomposition including a compound of the present invention and apharmaceutically acceptable excipient.

A. Formulation

The compositions of the present invention can be prepared in a widevariety of oral, parenteral and topical dosage forms. Oral preparationsinclude tablets, pills, powder, dragees, capsules, liquids, lozenges,cachets, gels, syrups, slurries, suspensions, etc., suitable foringestion by the patient. The compositions of the present invention canalso be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compositions described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompositions of the present invention can be administered transdermally.The compositions of this invention can also be administered byintraocular, intravaginal, and intrarectal routes includingsuppositories, insufflation, powders and aerosol formulations (forexamples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111,1995). Accordingly, the present invention also provides pharmaceuticalcompositions including a pharmaceutically acceptable carrier orexcipient and a compound of the present invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. Details ontechniques for formulation and administration are well described in thescientific and patent literature, see, e.g., the latest edition ofRemington's Pharmaceutical Sciences, Maack Publishing Co, Easton Pa.(“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5% or 10% to70% of the compounds of the present invention.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can contain thecompounds of the present invention mixed with a filler or binders suchas lactose or starches, lubricants such as talc or magnesium stearate,and, optionally, stabilizers. In soft capsules, the compounds of thepresent invention may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycol withor without stabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the compoundsof the present invention are dispersed homogeneously therein, as bystirring. The molten homogeneous mixture is then poured into convenientsized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe compounds of the present invention in water and adding suitablecolorants, flavors, stabilizers, and thickening agents as desired.Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partialester derived from a fatty acid and a hexitol (e.g., polyoxyethylenesorbitol mono-oleate), or a condensation product of ethylene oxide witha partial ester derived from fatty acid and a hexitol anhydride (e.g.,polyoxyethylene sorbitan mono-oleate). The aqueous suspension can alsocontain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose, aspartame orsaccharin. Formulations can be adjusted for osmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending the compounds of thepresent invention in a vegetable oil, such as arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin;or a mixture of these. The oil suspensions can contain a thickeningagent, such as beeswax, hard paraffin or cetyl alcohol. Sweeteningagents can be added to provide a palatable oral preparation, such asglycerol, sorbitol or sucrose. These formulations can be preserved bythe addition of an antioxidant such as ascorbic acid. As an example ofan injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997. The pharmaceutical formulations of the invention canalso be in the form of oil-in-water emulsions. The oily phase can be avegetable oil or a mineral oil, described above, or a mixture of these.Suitable emulsifying agents include naturally-occurring gums, such asgum acacia and gum tragacanth, naturally occurring phosphatides, such assoybean lecithin, esters or partial esters derived from fatty acids andhexitol anhydrides, such as sorbitan mono-oleate, and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan mono-oleate. The emulsion can also containsweetening agents and flavoring agents, as in the formulation of syrupsand elixirs. Such formulations can also contain a demulcent, apreservative, or a coloring agent.

The compositions of the present invention can also be delivered asmicrospheres for slow release in the body. For example, microspheres canbe formulated for administration via intradermal injection ofdrug-containing microspheres, which slowly release subcutaneously (seeRao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable andinjectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863,1995); or, as microspheres for oral administration (see, e.g., Eyles, J.Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermalroutes afford constant delivery for weeks or months.

In another embodiment, the compositions of the present invention can beformulated for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the formulationcan be a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension can be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the formulations of the compositions of thepresent invention can be delivered by the use of liposomes which fusewith the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the compositions of the present invention into the targetcells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306,1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J.Hosp. Pharm. 46:1576-1587, 1989).

Lipid-based drug delivery systems include lipid solutions, lipidemulsions, lipid dispersions, self-emulsifying drug delivery systems(SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). Inparticular, SEDDS and SMEDDS are isotropic mixtures of lipids,surfactants and co-surfactants that can disperse spontaneously inaqueous media and form fine emulsions (SEDDS) or microemulsions(SMEDDS). Lipids useful in the formulations of the present inventioninclude any natural or synthetic lipids including, but not limited to,sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters,glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®,Capryol®, Capmul®, Captex®, and Peceol®.

B. Administration

The compounds and compositions of the present invention can be deliveredby any suitable means, including oral, parenteral and topical methods.Transdermal administration methods, by a topical route, can beformulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the compounds and compositions of the presentinvention. The unit dosage form can be a packaged preparation, thepackage containing discrete quantities of preparation, such as packetedtablets, capsules, and powders in vials or ampoules. Also, the unitdosage form can be a capsule, tablet, cachet, or lozenge itself, or itcan be the appropriate number of any of these in packaged form.

The compounds and compositions of the present invention can beco-administered with other agents. Co-administration includesadministering the compound or composition of the present inventionwithin 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the otheragent. Co-administration also includes administering simultaneously,approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30minutes of each other), or sequentially in any order. Moreover, thecompounds and compositions of the present invention can each beadministered once a day, or two, three, or more times per day so as toprovide the preferred dosage level per day.

In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding the compounds and compositions of the present invention andany other agent. Alternatively, the various components can be formulatedseparately.

The compounds and compositions of the present invention, and any otheragents, can be present in any suitable amount, and can depend on variousfactors including, but not limited to, weight and age of the subject,state of the disease, etc. Suitable dosage ranges include from about 0.1mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg toabout 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about250 mg. Suitable dosages also include about 1 mg, 5, 10, 20, 30, 40, 50,60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg.

The composition can also contain other compatible therapeutic agents.The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in modulating aglucocorticoid receptor, or with adjunctive agents that may not beeffective alone, but may contribute to the efficacy of the active agent.

V. Method of Modulating a Glucocorticoid Receptor and Treating aDisorder

In some embodiments, the present invention provides a method ofmodulating a glucocorticoid receptor including contacting aglucocorticoid receptor with a compound of the present invention,thereby modulating the glucocorticoid receptor.

In some embodiments, the present invention provides a method of treatinga disorder through antagonizing a glucocorticoid receptor, includingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of the present invention, thereby treating thedisorder.

In some other embodiments, the present invention provides a method oftreating a disorder through antagonizing a glucocorticoid receptor, themethod including administering to a subject in need of such treatment,an effective amount of the compound of the present invention, therebytreating the disorder.

In an exemplary embodiment, the GR modulator is an antagonist of GRactivity (also referred to herein as “a glucocorticoid receptorantagonist”). A glucocorticoid receptor antagonist, as used herein,refers to any composition or compound which partially or completelyinhibits (antagonizes) the binding of a glucocorticoid receptor (GR)agonist (e.g. cortisol and synthetic or natural cortisol analog) to a GRthereby inhibiting any biological response associated with the bindingof a GR to the agonist.

In a related embodiment, the GR modulator is a specific glucocorticoidreceptor antagonist. As used herein, a specific glucocorticoid receptorantagonist refers to a composition or compound which inhibits anybiological response associated with the binding of a GR to an agonist bypreferentially binding to the GR rather than another nuclear receptor(NR). In some embodiments, the specific glucocorticoid receptorantagonist binds preferentially to GR rather than the mineralocorticoidreceptor (MR) or progesterone receptor (PR). In an exemplary embodiment,the specific glucocorticoid receptor antagonist binds preferentially toGR rather than the mineralocorticoid receptor (MR). In another exemplaryembodiment, the specific glucocorticoid receptor antagonist bindspreferentially to GR rather than the progesterone receptor (PR).

In a related embodiment, the specific glucocorticoid receptor antagonistbinds to the GR with an association constant (K_(d)) that is at least10-fold less than the K_(d) for other nuclear receptor. In anotherembodiment, the specific glucocorticoid receptor antagonist binds to theGR with an association constant (K_(d)) that is at least 100-fold lessthan the K_(d) for the other nuclear receptor. In another embodiment,the specific glucocorticoid receptor antagonist binds to the GR with anassociation constant (K_(d)) that is at least 1000-fold less than theK_(d) for the other nuclear receptor.

Examples of disorders or conditions suitable for use with presentinvention include, but are not limited to, obesity, diabetes,cardiovascular disease, hypertension, Syndrome X, depression, anxiety,glaucoma, human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS), neurodegeneration, Alzheimer'sdisease, Parkinson's disease, Huntington's disease, cognitionenhancement, Cushing's Syndrome, Addison's Disease, osteoporosis,frailty, muscle frailty, inflammatory diseases, osteoarthritis,rheumatoid arthritis, asthma and rhinitis, adrenal function-relatedailments, viral infection, immunodeficiency, immunomodulation,autoimmune diseases, allergies, wound healing, compulsive behavior,multi-drug resistance, addiction, psychosis, anorexia, cachexia,post-traumatic stress disorder, post-surgical bone fracture, medicalcatabolism, major psychotic depression, mild cognitive impairment,psychosis, dementia, hyperglycemia, central serous retinopathy, alcoholdependence, stress disorders, antipsychotic induced weight gain,delirium, cognitive impairment in depressed patients, cognitivedeterioration in individuals with Down's syndrome, psychosis associatedwith interferon-alpha therapy, chronic pain, pain associated withgastroesophageal reflux disease, postpartum psychosis, postpartumdepression, neurological disorders in premature infants, migraineheadaches, and cancers such as ovarian, breast and prostate cancer. Insome embodiments, the disorder or condition can be major psychoticdepression, stress disorders or antipsychotic induced weight gain. Inother embodiments, the disorder or condition can be Cushing's Syndrome.

A. Binding Assays

GR modulators of this invention can be tested for binding activity in avariety of assays. For example, by screening for the ability to competewith a GR ligand, such as dexamethasone, for binding to theglucocorticoid receptor. Those of skill in the art will recognize thatthere are a number of ways to perform such competitive binding assays.In some embodiments, GR is pre-incubated with a labeled GR ligand andthen contacted with a test compound. This type of competitive bindingassay may also be referred to herein as a binding displacement assay.Alteration (e.g., a decrease) of the quantity of ligand bound to GRindicates that the molecule is a potential GR modulator. Alternatively,the binding of a test compound to GR can be measured directly with alabeled test compound. This latter type of assay is called a directbinding assay.

Both direct binding assays and competitive binding assays can be used ina variety of different formats. The formats may be similar to those usedin immunoassays and receptor binding assays. For a description ofdifferent formats for binding assays, including competitive bindingassays and direct binding assays, see Basic and Clinical Immunology 7thEdition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E. T.Maggio, ed., CRC Press, Boca Raton, Fla. (1980); and “Practice andTheory of Enzyme Immunoassays,” P. Tijssen, Laboratory Techniques inBiochemistry and Molecular Biology, Elsevier Science Publishers B.V.Amsterdam (1985), each of which is incorporated herein by reference.

In solid phase competitive binding assays, for example, the samplecompound can compete with a labeled analyte for specific binding siteson a binding agent bound to a solid surface. In this type of format, thelabeled analyte can be a GR ligand and the binding agent can be GR boundto a solid phase. Alternatively, the labeled analyte can be labeled GRand the binding agent can be a solid phase GR ligand. The concentrationof labeled analyte bound to the capture agent is inversely proportionalto the ability of a test compound to compete in the binding assay.

Alternatively, the competitive binding assay may be conducted in liquidphase, and any of a variety of techniques known in the art may be usedto separate the bound labeled protein from the unbound labeled protein.For example, several procedures have been developed for distinguishingbetween bound ligand and excess bound ligand or between bound testcompound and the excess unbound test compound. These includeidentification of the bound complex by sedimentation in sucrosegradients, gel electrophoresis, or gel isoelectric focusing;precipitation of the receptor-ligand complex with protamine sulfate oradsorption on hydroxylapatite; and the removal of unbound compounds orligands by adsorption on dextran-coated charcoal (DCC) or binding toimmobilized antibody. Following separation, the amount of bound ligandor test compound is determined.

Alternatively, a homogenous binding assay may be performed in which aseparation step is not needed. For example, a label on the GR may bealtered by the binding of the GR to its ligand or test compound. Thisalteration in the labeled GR results in a decrease or increase in thesignal emitted by label, so that measurement of the label at the end ofthe binding assay allows for detection or quantitation of the GR in thebound state. A wide variety of labels may be used. The component may belabeled by any one of several methods. Useful radioactive labels includethose incorporating ³H, ¹²⁵I, ³⁵S, ¹⁴C, or ³²P. Useful non-radioactivelabels include those incorporating fluorophores, chemiluminescentagents, phosphorescent agents, electrochemiluminescent agents, and thelike. Fluorescent agents are especially useful in analytical techniquesthat are used to detect shifts in protein structure such as fluorescenceanisotropy and/or fluorescence polarization. The choice of label dependson sensitivity required, ease of conjugation with the compound,stability requirements, and available instrumentation. For a review ofvarious labeling or signal producing systems which may be used, see U.S.Pat. No. 4,391,904, which is incorporated herein by reference in itsentirety for all purposes. The label may be coupled directly orindirectly to the desired component of the assay according to methodswell known in the art.

High-throughput screening methods may be used to assay a large number ofpotential modulator compounds. Such “compound libraries” are thenscreened in one or more assays, as described herein, to identify thoselibrary members (particular chemical species or subclasses) that displaya desired characteristic activity. Preparation and screening of chemicallibraries is well known to those of skill in the art. Devices for thepreparation of chemical libraries are commercially available (see, e.g.,357 MPS, 390 MPS, Advanced Chem Tech, Louisville Ky., Symphony, Rainin,Woburn, Mass., 433A Applied Biosystems, Foster City, Calif., 9050 Plus,Millipore, Bedford, Mass.).

B. Cell-Based Assays

Cell-based assays involve whole cells or cell fractions containing GR toassay for binding or modulation of activity of GR by a compound of thepresent invention. Exemplary cell types that can be used according tothe methods of the invention include, e.g., any mammalian cellsincluding leukocytes such as neutrophils, monocytes, macrophages,eosinophils, basophils, mast cells, and lymphocytes, such as T cells andB cells, leukemias, Burkitt's lymphomas, tumor cells (including mousemammary tumor virus cells), endothelial cells, fibroblasts, cardiaccells, muscle cells, breast tumor cells, ovarian cancer carcinomas,cervical carcinomas, glioblastomas, liver cells, kidney cells, andneuronal cells, as well as fungal cells, including yeast. Cells can beprimary cells or tumor cells or other types of immortal cell lines. Ofcourse, GR can be expressed in cells that do not express an endogenousversion of GR.

In some cases, fragments of GR, as well as protein fusions, can be usedfor screening. When molecules that compete for binding with GR ligandsare desired, the GR fragments used are fragments capable of binding theligands (e.g., dexamethasone). Alternatively, any fragment of GR can beused as a target to identify molecules that bind GR. GR fragments caninclude any fragment of, e.g., at least 20, 30, 40, 50 amino acids up toa protein containing all but one amino acid of GR.

In some embodiments, signaling triggered by GR activation is used toidentify GR modulators. Signaling activity of GR can be determined inmany ways. For example, downstream molecular events can be monitored todetermine signaling activity. Downstream events include those activitiesor manifestations that occur as a result of stimulation of a GRreceptor. Exemplary downstream events useful in the functionalevaluation of transcriptional activation and antagonism in unalteredcells include upregulation of a number of glucocorticoid responseelement (GRE)-dependent genes (PEPCK, tyrosine amino transferase,aromatase). In addition, specific cell types susceptible to GRactivation may be used, such as osteocalcin expression in osteoblastswhich is downregulated by glucocorticoids; primary hepatocytes whichexhibit glucocorticoid mediated upregulation of PEPCK andglucose-6-phosphate (G-6-Pase)). GRE-mediated gene expression has alsobeen demonstrated in transfected cell lines using well-knownGRE-regulated sequences (e.g. the mouse mammary tumor virus promoter(MMTV) transfected upstream of a reporter gene construct). Examples ofuseful reporter gene constructs include luciferase (luc), alkalinephosphatase (ALP) and chloramphenicol acetyl transferase (CAT). Thefunctional evaluation of transcriptional repression can be carried outin cell lines such as monocytes or human skin fibroblasts. Usefulfunctional assays include those that measure IL-1beta stimulated IL-6expression; the downregulation of collagenase, cyclooxygenase-2 andvarious chemokines (MCP-1, RANTES); LPS stimulated cytokine release,e.g., TNFα; or expression of genes regulated by NFkB or AP-1transcription factors in transfected cell-lines.

Typically, compounds that are tested in whole-cell assays are alsotested in a cytotoxicity assay. Cytotoxicity assays are used todetermine the extent to which a perceived modulating effect is due tonon-GR binding cellular effects. In an exemplary embodiment, thecytotoxicity assay includes contacting a constitutively active cell withthe test compound. Any decrease in cellular activity indicates acytotoxic effect.

C. Specificity

The compounds of the present invention may be subject to a specificityassay (also referred to herein as a selectivity assay). Typically,specificity assays include testing a compound that binds GR in vitro orin a cell-based assay for the degree of binding to non-GR proteins.Selectivity assays may be performed in vitro or in cell based systems,as described above. Binding may be tested against any appropriate non-GRprotein, including antibodies, receptors, enzymes, and the like. In anexemplary embodiment, the non-GR binding protein is a cell-surfacereceptor or nuclear receptor. In another exemplary embodiment, thenon-GR protein is a steroid receptor, such as estrogen receptor,progesterone receptor, androgen receptor, or mineralocorticoid receptor.

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding equivalents of thefeatures shown and described, or portions thereof, it being recognizedthat various modifications are possible within the scope of theinvention claimed. Moreover, any one or more features of any embodimentof the invention may be combined with any one or more other features ofany other embodiment of the invention, without departing from the scopeof the invention. For example, the features of the GR modulatorcompounds are equally applicable to the methods of treating diseasestates and/or the pharmaceutical compositions described herein. Allpublications, patents, and patent applications cited herein are herebyincorporated by reference in their entirety for all purposes.

VI. Examples

Structures are named according to standard IUPAC nomenclature using theCambridgeSoft ChemDraw naming package.

¹H NMR spectra were recorded at ambient temperature using a BrukerAvance III spectrometer (400 MHz).

Mass spectrometry (LCMS) experiments to determine retention times andassociated mass ions were performed as follows: experiments wereperformed using an Agilent Infinity 1260 LC 6120 quadrupole massspectrometer with positive and negative ion electrospray and ELS/UV @254 nm detection using an Agilent Zorbax Extend C18, Rapid Resolution HT1.8 micron C18 30×4.6 mm column and a 2.5 mL/minute flow rate. Theinitial solvent system was 95% water containing 0.1% formic acid(solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B)ramping up to 5% solvent A and 95% solvent B over the next 3.0 minutes,the flow rate was then increased to 4.5 mL/minute and held for 0.5minutes at 95% B. Over 0.1 minute the gradient was returned to 95% A and5% B and 3.5 mL/minute and was held at these conditions for 0.3 minutes;the final 0.1 minute resulted in the return to the initial startingconditions, 95% A 5% B at 2.5 mL/minute.

Intermediate 1A. (4aR,8aS)-methyl1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-d]isoquinoline-4a-carboxylate

A solution of (4aR,8aS)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(WO 2005087769; 0.35 g, 0.815 mmol) in HCl (4M solution in dioxane)(4.07 ml, 16.30 mmol) was stirred at room temperature for 1 hour, thensolvent was evaporated to give a white solid. This material wasdissolved in dichloromethane (10 ml), and Hunig's Base (0.712 ml, 4.07mmol), then 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.239 g,0.978 mmol) were added. The reaction mixture was stirred at roomtemperature for 4 days, before solvent was evaporated, and the crudeproduct was purified by column chromatography on silica gel (gradient:20-40% ethyl acetate in isohexane) to afford (4aR,8aS)-methyl1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(0.38 g) as a colourless gum, LCMS: RT 2.66 min, m+H=538.0.

The following intermediates were similarly prepared from appropriatestarting materials:

Intermediate 1B. (4aR,8aS)-methyl6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS: RT 3.12 min, m+H=538.1/540.1

Intermediate 1C. (4aR,8aS)-methyl6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate

LCMS: RT 2.80 min, m+H=506.0.

Intermediate 2A. (4aR,8aS)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

2-Bromopyridine (0.690 ml, 7.10 mmol) in dry tetrahydrofuran (5 ml) wasadded to butyllithium (2.5M in hexanes) (2.91 ml, 7.28 mmol) in drytetrahydrofuran (3 ml) at −78° C. The reaction mixture was stirred at−78° C. for 45 minutes. A solution of (4aR,8aS)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(1.0 g, 2.328 mmol) in dry tetrahydrofuran (8 ml) was added dropwise andthe reaction mixture was stirred for 45 minutes at −78° C. Water (10 ml)was added and the reaction mixture was stirred at room temperature for10 minutes. The aqueous phase was extracted with ethyl acetate (2×10ml). The combined organic phases were washed with brine (10 ml), dried(magnesium sulfate), and the solvent removed to give a brown oil. Thecrude product was purified by column chromatography on silica gel(gradient: 10-70% ethyl acetate in isohexane) to afford(4aR,8aS)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(766 mg) as a pale yellow solid, LCMS: RT 2.70 min, m+H=477.

The following intermediates were similarly prepared from appropriatestarting materials:

Intermediate 2B. (4aR,8aS)-tert-butyl1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)picolinoyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS: RT 2.88 min, m+H=545.3.

Intermediate 2C. (4aR,8aS)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

Using diethyl ether as solvent in place of tetrahydrofuran. LCMS: RT2.67 min, m+H=482.9.

Intermediate 2D. (R)-tert-butyl1-(4-fluorophenyl)-4a-(4-methylpicolinoyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

LCMS: RT 2.77 min, m+H=491.3.

Intermediate 2E. (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-5-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

Using diethyl ether as solvent in place of tetrahydrofuran. LCMS: RT2.51 min, m+H=483.2.

Intermediate 3A. 4-(benzylthio)-1H-1,2,3-triazole

Benzyl bromide (11.79 ml, 99 mmol) was added dropwise to a solution ofsodium 1H-1,2,3-triazole-4-thiolate (12.2 g, 99 mmol) in ethanol (100ml) at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred for 20 minutes. The reaction mixture was dilutedwith ethyl acetate (100 ml) and washed with water (100 ml), brine (100ml) and dried (sodium sulfate). The solvent was removed to give4-(benzylthio)-1H-1,2,3-triazole (16.9 g) as a white solid, LCMS: RT1.66 min, m+H=191; 1H NMR (400 MHz, CDCl₃): δ 9.72 (1H, v br s), 7.47(1H, s), 7.30-7.21 (5H, m), 4.12 (2H, s).

Intermediate 3B. 2-(Benzylthio)-6-(trifluoromethyl)pyridine

To a suspension of sodium hydride (0.170 g, 4.24 mmol) intetrahydrofuran (10 ml) was added benzylthiol (0.338 ml, 2.88 mmol)dropwise at 0° C. The reaction mixture was stirred at 0° C. for 15minutes then 2-fluoro-6-(trifluoromethyl)pyridine (0.365 ml, 3.03 mmol)was added dropwise. The reaction mixture was stirred at 0° C. for 30minutes. Methanol (1 ml) was added carefully and the reaction mixturewas stirred at 0° C. for a further 10 minutes then water (5 ml) anddichloromethane (10 ml) were added. The organic layer was recoveredusing a phase separator cartridge then concentrated in vacuo to give2-(benzylthio)-6-(trifluoromethyl)pyridine (538 mg) as a colourless oil.LCMS: RT 2.80 min, m+H=270.1.

Intermediate 4A. 4-(Benzylthio)-2-methyl-2H-1,2,3-triazole

Iodomethane (2.409 ml, 38.7 mmol) was added dropwise to a mixture of4-(benzylthio)-1H-1,2,3-triazole (3.7 g, 19.35 mmol) and potassiumcarbonate (5.88 g, 42.6 mmol) in N,N-dimethylformamide (40 ml) at 0° C.The reaction mixture was then allowed to warm to room temperature andstirred for 1 hour. Water (40 ml) and ethyl acetate (40 ml) were addedand the phases separated. The organic phase was washed with water (2×40ml), brine (40 ml), dried (sodium sulfate) and solvent was removed togive a yellow oil. The crude product was purified by columnchromatography on silica gel (gradient: 0-100% ethyl acetate inisohexane) to afford 4-(benzylthio)-2-methyl-2H-1,2,3-triazole (1.61 g)as the major and first-eluting regioisomeric product, as a colourlessoil, LCMS: RT 2.05 min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 7.68 (1H,s), 7.35-7.19 (5H, m), 4.18 (2H, s), 4.11 (3H, s).

Intermediate 4B. 4-(Benzylthio)-1-methyl-1H-1,2,3-triazole

Obtained as a pale yellow oil (883 mg) as the third-elutingregioisomeric product from the reaction above. LCMS: RT 1.68 min,m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 8.02 (1H, s), 7.34-7.19 (5H, m),4.12 (2H, s), 4.00 (3H, s).

The following intermediates were similarly prepared from appropriatestarting materials:

Intermediate 4C. 4-(Benzylthio)-2-propyl-2H-1,2,3-triazole

Obtained as the major, first-eluting regioisomeric product. LCMS: RT2.36 min, m+H=234.2; 1H NMR (400 MHz, DMSO-d6): δ 7.69 (1H, s),7.28-7.27 (4H, m), 7.25-7.20 (1H, m), 4.32 (2H, t, J=7.0 Hz), 4.18 (2H,s), 1.83 (2H, sext, J=7.0 Hz), 0.78 (3H, t, J=7.0 Hz).

Intermediate 4D. 4-(Benzylthio)-2-isopropyl-2H-1,2,3-triazole

Obtained as the major, first-eluting regioisomeric product. LCMS: RT2.41 min, m+H=234; 1H NMR (400 MHz, DMSO-d6): δ 7.67 (1H, s), 7.31-7.21(5H, m), 4.76 (1H, sept, J=6.7 Hz), 4.17 (2H, s), 1.44 (6H, d, J=6.7Hz).

Intermediate 4E. 4-(Benzylthio)-2-ethyl-2H-1,2,3-triazole

Obtained as the major, first-eluting regioisomeric product. LCMS: RT2.24 min, m+H=220; 1H NMR (400 MHz, DMSO-d6): δ 7.69 (1H, s), 7.32-7.21(5H, m), 4.39 (2H, q, J=7.3 Hz), 4.18 (2H, s), 1.40 (3H, t, J=7.3 Hz).

Intermediate 4F. 4-(Benzylthio)-1-methyl-1H-1,2,3-triazole

Obtained as a minor, second-eluting regioisomeric product. LCMS: RT 1.79min, m+H=206; 1H NMR (400 MHz, DMSO-d6): δ 7.71 (1H, s), 7.36-7.23 (3H,m), 7.22-7.14 (2H, m), 4.09 (2H, s), 3.73 (3H, s).

Intermediate 4G. 1-propyl-1H-1,2,3-triazole-5-sulfonyl chloride

Obtained as a minor, second-eluting regioisomeric product. LCMS: RT 2.08min, m+H=234.2; 1H NMR (400 MHz, DMSO-d6): δ 7.74 (1H, s), 7.38-7.12(5H, m), 4.13 (2H, s), 4.06 (2H, t, J=7.0 Hz), 1.66 (2H, sext, J=7.0Hz), 0.74 (3H, t, J=7.0 Hz).

Intermediate 4H. 4-(benzylthio)-1-isopropyl-1H-1,2,3-triazole

Obtained as a minor, third-eluting regioisomeric product. LCMS: RT 1.99min, m+H=234; 1H NMR (400 MHz, DMSO-d6): δ 8.10 (1H, s), 7.30-7.18 (5H,m), 4.76 (1H, sept, J=6.7 Hz), 4.10 (2H, s), 1.43 (6H, d, J=6.7 Hz).

Intermediate 5A. 2-Methyl-2H-1,2,3-triazole-4-sulfonyl chloride

N-chlorosuccinimide (3.38 g, 25.3 mmol) was added to a solution of4-(benzylthio)-2-methyl-2H-1,2,3-triazole (1.3 g, 6.33 mmol) in aceticacid (32 ml) and water (16 ml) and the resultant mixture was stirred atroom temperature for 1 hour. Water (40 ml) was added and the mixture wasextracted with ethyl acetate (40 ml). The organic phase was washed withsaturated aqueous sodium hydrogen carbonate solution (40 ml), brine (40ml), dried (magnesium sulfate), and the solvent removed to give2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride (1.35 g) as a pale yellowoil. LCMS (quenching into morpholine): RT 1.09 min,m+H+morpholine-Cl=233.1; 1H NMR (400 MHz, CDCl3): δ 8.11 (1H, s), 4.36(3H, s).

The following intermediates were similarly prepared from appropriatestarting materials:

Intermediate 5B. 1-Methyl-1H-1,2,3-triazole-4-sulfonyl chloride

LCMS (quenching into morpholine): RT 0.86 min, m+H+morpholine-Cl=233.1;1H NMR (400 MHz, CDCl3): δ 8.22 (1H, s), 4.25 (3H, s).

Intermediate 5C. 2-Propyl-2H-1,2,3-triazole-4-sulfonyl chloride

LCMS (quenching into morpholine): RT 1.62 min, m+H+morpholine-Cl=261.2;1H NMR (400 MHz, CDCl3): δ 8.11 (1H, s), 4.53 (2H, t, J=7.1 Hz), 2.08(2H, sext, J=7.1 Hz), 0.98 (3H, t, J=7.1 Hz).

Intermediate 5D. 2-Isopropyl-2H-1,2,3-triazole-4-sulfonyl chloride

LCMS (quenching into morpholine): RT 1.64 min, m+H+morpholine-Cl=261; 1HNMR (400 MHz, CDCl3): δ 7.62 (1H, s), 4.76 (1H, sept., J=6.7 Hz), 1.46(6H, d, J=6.7 Hz).

Intermediate 5E. 2-Ethyl-2H-1,2,3-triazole-4-sulfonyl chloride

LCMS (quenching into morpholine): RT 1.37 min, m+H+morpholine-Cl=247; 1HNMR (400 MHz, CDCl3): δ 8.11 (1H, s), 4.62 (2H, q, J=7.4 Hz), 1.66 (3H,t, J=7.4 Hz).

Intermediate 5F. 6-(Trifluoromethyl)pyridine-2-sulfonyl chloride

LCMS (quenching into morpholine): RT 1.84 min, m+H+morpholine-Cl=297.1.

Intermediate 5G. 1-methyl-1H-1,2,3-triazole-5-sulfonyl chloride

Chlorine gas was bubbled through a solution of4-(benzylthio)-1-methyl-1H-1,2,3-triazole (200 mg, 0.974 mmol) indichloromethane (15 ml) and water (3 ml) for 2 minutes at 0° C. then thereaction mixture was stirred at 0° C. for a further 5 minutes. Water (10ml) was added and the mixture was extracted with dichloromethane (10ml). The organic phase was dried over magnesium sulfate, filtered andconcentrated in vacuo to give 1-methyl-1H-1,2,3-triazole-5-sulfonylchloride (317 mg) as a colourless oil. LCMS (quenching into morpholine):RT 1.17 min, m+H+morpholine-Cl=233.1; 1H NMR (400 MHz, CDCl3): δ 8.27(1H, s), 4.40 (3H, s).

The following intermediates was similarly prepared from appropriatestarting materials:

Intermediate 5H. 1-propyl-1H-1,2,3-triazole-5-sulfonyl chloride

LCMS (quenching into morpholine): RT 1.58 min, m+H+morpholine-Cl=261.1;1H NMR (400 MHz, CDCl3): δ 8.27 (1H, s), 4.68-4.64 (2H, m), 2.12 (2H,sext, J=7.1 Hz), 1.05 (3H, t, J=7.1 Hz).

Intermediate 5I. 3-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride

3-Fluoro-4-(trifluoromethyl)aniline (5 g, 27.9 mmol) was dissolved inacetonitrile (10 ml), cooled to 0° C., and treated with tetrafluoroboricacid (48% aqueous solution, 6.49 ml, 41.9 mmol) and tert-butyl nitrite(4.98 ml, 41.9 mmol). The reaction mixture was maintained at 0° C. for 1hour. In the meantime, a suspension of copper (I) chloride (4.15 g, 41.9mmol) in acetonitrile (40 ml) at 0° C. was saturated with sulfur dioxidegas by bubbling the gas through the suspension with vigorous stirringfor 30 minutes. When the diazotization reaction was complete after 1hour, this solution was added dropwise to the suspension of copper (I)chloride, causing vigorous evolution of gas. The reaction mixture wasthen allowed to warm to room temperature and stirred for 1 hour, afterwhich time it was poured onto 100 ml of an ice/water slurry. Diethylether (150 ml) was added, causing a precipitate to form, which wasremoved by filtration. The filtrate was washed with water (100 ml) andbrine (100 ml), dried over magnesium sulfate, filtered, and concentratedin vacuo to give 3-fluoro-4-(trifluoromethyl)benzene-1-sulfonyl chloride(6.62 g) as an orange oil. LCMS (quenching into morpholine): RT 2.25min, m+H+morpholine-Cl=314.1.

Intermediate 5J. 1-isopropyl-1H-1,2,3-triazole-4-sulfonyl chloride

N-chlorosuccinimide (0.458 g, 3.43 mmol) was added to a solution of4-(benzylthio)-1-isopropyl-1H-1,2,3-triazole (0.20 g, 0.857 mmol) inacetic acid (6 ml) and water (3 ml) and the resultant mixture wasstirred at room temperature for 1 hour. Water (8 ml) was added and themixture was extracted with ethyl acetate (8 ml). The organic phase waswashed with saturated aqueous sodium hydrogen carbonate solution (8 ml),brine (8 ml), dried (magnesium sulfate), and the solvent removed to give1-isopropyl-1H-1,2,3-triazole-4-sulfonyl chloride (311 mg) as acolourless oil. LCMS (quenching into morpholine): RT 1.47 min,m+H+morpholine-Cl=261; 1H NMR (400 MHz, CDCl3): δ 8.26 (1H, s), 4.95(1H, sept., J=6.7 Hz), 1.68 (6H, d, J=6.7 Hz).

The following intermediates was similarly prepared from appropriatestarting materials:

Intermediate 5K. 2H-1,2,3-triazole-4-sulfonyl chloride

LCMS (quenching into morpholine): RT 1.64 min, m+H+morpholine-Cl=219.1;1H NMR (400 MHz, CDCl3): δ 9.06 (1H, br s), 8.31 (1H, s).

Intermediate 6A. (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

A solution of 4-bromo-2-(trimethylsilyl)thiazole (3.00 g, 12.70 mmol) indry ether (3 mL) was added to a solution of isopropylmagnesium chloride2M in tetrahydrofuran (6.35 ml, 12.70 mmol) in dry ether (16 mL) at 0°C. The resulting suspension was stirred at 0° C. for 50 minutes. Asolution of (R)-6-tert-butyl 4a-methyl1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate(1.81 g, 4.23 mmol) in dry ether:tetrahydrofuran (4:1; total volume 15mL) was added dropwise to the suspension at 0° C., and the reactionmixture was stirred for 3.5 hours at room temperature. Water (50 mL) wasadded and the reaction mixture was stirred at room temperature for 10minutes. The aqueous layer was extracted with ethyl acetate (3×50 mL).The combined organic extracts were washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to give an orangeoil. The crude orange oil was diluted with acetonitrile (30 mL) and 1 MHCl (4.2 mL), and stirred at room temperature for 45 minutes. Thereaction was diluted with ethyl acetate (100 mL) and washed sequentiallywith brine (50 mL), saturated aqueous sodiumhydrogen carbonate solution(50 mL) then brine (50 mL). The organic layer was dried over magnesiumsulfate and concentrated in vacuo to give an orange oil. The crudeproduct was purified by column chromatography on silica gel (gradient:0-45% ethyl acetate in isohexane) to afford (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateas a pale yellow foamy solid (932 mg). LCMS (Method F, ES-API): RT 2.55min, m+H=481.0.

Intermediate 7A. (4aR,8aS)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate

A solution of (R)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(420 mg, 0.874 mmol) in methanol (40 mL) was hydrogenated in the H-Cube(10% Palladium/Carbon, 30×4 mm, Full hydrogen, 55° C., 1 mL/min). Thesolvent was removed to give (4aR,8aS)-tert-butyl1-(4-fluorophenyl)-4a-(thiazole-4-carbonyl)-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylateas an orange solid (385 mg). LCMS (Method F, ES-API): RT 2.51 min,m+H=483.2.

Example 1A((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of 2-bromopyridine (0.109 ml, 1.116 mmol) in drytetrahydrofuran (2 ml) was added to a solution of butyllithium (2.5M inhexanes) (0.417 ml, 1.042 mmol) in dry tetrahydrofuran (1.2 ml), and thereaction mixture stirred at −78° C. under nitrogen for 45 minutes. Asolution of (4aR,8aS)-methyl1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate(0.2 g, 0.372 mmol) in dry tetrahydrofuran (2 ml) was then addeddropwise. The reaction mixture was stirred at −78° C. for 45 minutes,then quenched by the addition of 10:1 methanol:acetic acid (5 ml), andstirred at room temperature for an additional 10 minutes. The mixturewas diluted with ethyl acetate (200 ml), washed with saturated aqueousammonium chloride solution (2×50 ml) and brine (50 ml), dried (magnesiumsulfate), filtered and evaporated to give a colourless gum. The crudeproduct was purified by column chromatography on silica gel (eluent: 10%ethyl acetate in dichloromethane) to afford((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(0.06 g) as a white solid, LCMS: RT 2.76 min, m+H=585.0; 1H NMR (400MHz, CDCl3): δ 8.60-8.56 (1H, m), 7.81-7.76 (4H, m), 7.70-7.65 (2H, m),7.48-7.39 (3H, m), 7.29 (1H, s), 7.16-7.10 (2H, m), 5.62 (1H, dd,J=12.3, 2.0 Hz), 4.27 (1H, d, J=16.2 Hz), 3.99-3.94 (1H, m), 3.40 (1H,dd, J=16.7, 11.2 Hz), 2.69 (1H, dd, J=16.4, 5.9 Hz), 2.56-2.40 (4H, m),1.79-1.68 (2H, m).

The following examples were similarly prepared from the appropriateintermediate:

Example 1B((4aR,8aS)-6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 3.34 min, m+H=584.8/586.8; 1H NMR (400 MHz, CDCl3): δ 8.56 (1H,dt, J=4.8, 1.3 Hz), 7.79-7.78 (2H, m), 7.72 (1H, d, J=1.9 Hz), 7.50-7.41(5H, m), 7.29 (1H, s), 7.17-7.11 (2H, m), 5.56 (1H, dd, J=12.3, 1.9 Hz),4.26 (1H, d, J=16.9 Hz), 3.98-3.94 (1H, m), 3.39 (1H, dd, J=16.0, 11.8Hz), 2.69 (1H, dd, J=16.1, 6.0 Hz), 2.58-2.40 (4H, m), 1.81-1.70 (2H,m).

Example 1C((4aR,8aS)-6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.63 min, m+H=553.0; 1H NMR (400 MHz, CDCl3): δ 8.60-8.59 (1H,m), 7.83-7.77 (2H, m), 7.50-7.40 (5H, m), 7.30 (1H, s), 7.25-7.18 (1H,m), 7.17-7.11 (2H, m), 5.57 (1H, dd, J=12.3, 2.0 Hz), 4.29 (1H, d,J=16.9 Hz), 3.95-3.92 (1H, m), 3.40 (1H, dd, J=16.0, 11.8 Hz), 2.69 (1H,dd, J=16.3, 6.0 Hz), 2.56-2.40 (4H, m), 1.80-1.68 (2H, m).

Example 2A((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

A solution of (4aR,8aS)-tert-butyl1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate(200 mg, 0.420 mmol) in 4M HCl/dioxane (2098 μl, 8.39 mmol) was stirredat room temperature for 45 minutes. The solvent was removed to give apale yellow solid, which was dissolved in dichloromethane (8 mL) anddiisopropylamine (367 μl, 2.098 mmol) and then2-propyl-2H-1,2,3-triazole-4-sulfonyl chloride (117 mg, 0.420 mmol) wasadded. The reaction mixture was stirred at room temperature for 15minutes, then the solvent was removed to give a brown oil. The crudeproduct was purified by column chromatography on silica gel (gradient:0-70% ethyl acetate in cyclohexane) to afford((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone(156 mg) as a white solid, LCMS: RT 2.60 min, m+H=550.0.; 1H NMR (400MHz, CDCl3): δ 8.66 (1H, ddd, J=4.7, 1.7, 0.9 Hz), 7.85-7.76 (3H, m),7.51-7.45 (2H, m), 7.43 (1H, ddd, J=7.1, 4.7, 1.7 Hz), 7.33 (1H, s),7.19-7.09 (2H, m), 5.68 (1H, dd, J=12.4, 2.1 Hz), 4.43 (2H, t, J=7.1Hz), 4.37 (1H, d, J=16.2 Hz), 4.00-3.93 (1H, m), 3.46 (1H, dd, J=16.2,11.1 Hz), 2.70 (1H, dd, J=16.2, 6.0 Hz), 2.64-2.36 (4H, m), 2.02 (2H,sextet, J=7.3 Hz), 1.79-1.71 (2H, m), 0.94 (3H, t, J=7.3 Hz).

The following examples were similarly prepared from the appropriateintermediate:

Example 2B((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.45 min, m+H=549.1; 1H NMR (400 MHz, CDCl3): δ 8.64 (1H, ddd,J=4.7, 1.7, 0.9 Hz), 7.85-7.82 (1H, m), 7.79 (1H, td, J=7.3, 1.7 Hz),7.70-7.64 (2H, m), 7.52-7.45 (2H, m), 7.43 (1H, ddd, J=7.3, 4.8, 1.5Hz), 7.33 (1H, s), 7.19-7.08 (2H, m), 5.52 (1H, dd, J=11.9, 2.1 Hz),4.35 (1H, d, J=16.2 Hz), 4.15-4.02 (2H, m), 3.88-3.81 (1H, m), 3.45 (1H,dd, J=15.5, 11.1 Hz), 2.69 (1H, dd, J=16.2, 6.0 Hz), 2.56 (1H, d, J=16.2Hz), 2.48-2.33 (2H, m), 2.26 (1H, d, J=11.9 Hz), 1.90 (2H, sextet, J=7.3Hz), 1.82-1.65 (2H, m), 0.91 (3H, t, J=7.3 Hz).

Example 2C((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS: RT 2.61 min, m+H=590.0; 1H NMR (400 MHz, CDCl3): δ 8.86 (1H, d,J=5.0 Hz), 8.10 (1H, s), 7.81 (1H, s), 7.70-7.62 (1H, m), 7.52-7.44 (2H,m), 7.33 (1H, s), 7.20-7.11 (2H, m), 5.64 (1H, dd, J=12.5, 2.0 Hz), 4.26(3H, s), 4.25 (1H, d, J=16.2 Hz), 4.02-3.90 (1H, m), 3.44 (1H, dd,J=16.2, 10.8 Hz), 2.73 (1H, dd, J=16.2, 5.9 Hz), 2.67-2.53 (3H, m), 2.43(1H, qd, J=13.2, 5.0 Hz), 1.88-1.75 (2H, m).

Example 2D((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS: RT 2.72 min, m+H=617.0; 1H NMR (400 MHz, CDCl3): δ 8.86 (1H, d,J=5.0 Hz), 8.13-8.08 (1H, m), 7.70-7.62 (3H, m), 7.51-7.42 (2H, m), 7.33(1H, s), 7.20-7.10 (2H, m), 5.49 (1H, dd, J=12.0, 2.0 Hz), 4.23 (1H, d,J=16.1 Hz), 4.09 (2H, t, J=7.2 Hz), 3.88-3.78 (1H, m), 3.43 (1H, dd,J=16.1, 11.0 Hz), 2.71 (1H, dd, J=16.3, 6.0 Hz), 2.60 (1H, d, J=16.3Hz), 2.49-2.32 (2H, m), 2.27 (1H, d, J=12.1 Hz), 1.90 (2H, sextet, J=7.2Hz), 1.83-1.68 (2H, m), 0.91 (3H, t, J=7.2 Hz).

Example 2E((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS: RT 2.45 min, m+H=554.9; 1H NMR (400 MHz, CDCl3): δ 8.04 (1H, d,J=3.1 Hz), 7.74 (1H, s), 7.69 (1H, d, J=0.5 Hz), 7.65 (1H, d, J=3.1 Hz),7.53-7.46 (2H, m), 7.40 (1H, s), 7.21-7.13 (2H, m), 5.47 (1H, dd,J=12.0, 2.1 Hz), 4.23 (1H, d, J=16.2 Hz), 4.12 (2H, t, J=7.2 Hz),3.94-3.85 (1H, m), 3.44 (1H, dd, J=16.2, 11.1 Hz), 2.72 (1H, dd, J=16.2,6.0 Hz), 2.62 (1H, d, J=16.2 Hz), 2.54-2.41 (2H, m), 2.36 (1H, d, J=12.1Hz), 1.95 (2H, sextet, J=7.3 Hz), 1.87-1.75 (2H, m), 0.95 (3H, t, J=7.3Hz).

Example 2F((4aR,8aS)-1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.65 min, m+H=534.9; 1H NMR (400 MHz, CDCl3): δ 8.66 (1H, ddd,J=4.7, 1.7, 1.0 Hz), 7.88-7.77 (2H, m), 7.53-7.43 (5H, m), 7.41-7.35(1H, m), 7.35 (1H, s), 7.29-7.22 (1H, m), 7.22-7.12 (2H, m), 5.62 (1H,dd, J=12.2, 2.1 Hz), 4.35 (1H, d, J=16.2 Hz), 3.98-3.86 (1H, m), 3.44(1H, dd, J=16.2, 11.1 Hz), 2.70 (1H, dd, J=16.2, 5.9 Hz), 2.56 (1H, d,J=16.2 Hz), 2.51-2.41 (2H, m), 2.39 (1H, d, J=12.2 Hz), 1.83-1.65 (2H,m).

Example 2G((4aR,8aS)-1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.79 min, m+H=584.9; 1H NMR (400 MHz, CDCl3): δ 8.66-8.61 (1H,m), 7.94 (1H, s), 7.88 (1H, br. d, J=7.9 Hz), 7.84-7.77 (3H, m), 7.61(1H, t, J=7.8 Hz), 7.53-7.41 (3H, m), 7.33 (1H, s), 7.21-7.11 (2H, m),5.66 (1H, dd, J=12.2, 2.1 Hz), 4.31 (1H, d, J=16.2 Hz), 4.03-3.91 (1H,m), 3.43 (1H, dd, J=16.2, 11.2 Hz), 2.71 (1H, dd, J=16.2, 5.9 Hz),2.62-2.35 (4H, m), 1.85-1.68 (2H, m).

Example 2H((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

Using trifluoroacetic acid/dichloromethane in place of HCl/dioxane.LCMS: RT 2.44 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.84 (1H, d,J=5.0 Hz), 8.10 (1H, m), 7.66-7.65 (3H, m), 7.50-7.45 (2H, m), 7.33 (1H,s), 7.18-7.12 (2H, m), 5.47 (1H, dd, J=11.8, 2.0 Hz), 4.22 (1H, d,J=16.2 Hz), 3.92 (3H, s), 3.85-3.83 (1H, m), 3.42 (1H, dd, J=16.5, 11.4Hz), 2.71 (1H, dd, J=16.5, 5.8 Hz), 2.60 (1H, d, J=16.2 Hz), 2.46-2.34(2H, m), 2.29 (1H, d, J=12.0 Hz), 1.84-1.70 (2H, m).

Example 2I((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

Using trifluoroacetic acid/dichloromethane in place of HCl/dioxane.LCMS: RT 2.49 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d,J=5.0 Hz), 8.10-8.09 (1H, m), 7.65-7.63 (1H, m), 7.50-7.45 (2H, m), 7.38(1H, d, J=2.5 Hz), 7.34 (1H, s), 7.18-7.12 (2H, m), 6.55 (1H, d, J=2.5Hz), 5.57 (1H, dd, J=11.8, 2.0 Hz), 4.27 (1H, d, J=16.2 Hz), 3.97 (3H,s), 3.93-3.89 (1H, m), 3.44 (1H, dd, J=16.2, 10.9 Hz), 2.71 (1H, dd,J=16.4, 6.0 Hz), 2.63-2.55 (2H, m), 2.54 (1H, d, J=12.2 Hz), 2.45-2.34(1H, m), 1.82-1.74 (2H, m).

Example 2J((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

Using trifluoroacetic acid/dichloromethane in place of HCl/dioxane.LCMS: RT 2.60 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.77 (1H, d,J=4.9 Hz), 8.07-8.06 (1H, m), 7.66-7.64 (1H, m), 7.49-7.44 (2H, m), 7.30(1H, d, J=2.0 Hz), 7.29 (1H, s), 7.18-7.12 (2H, m), 6.60 (1H, d, J=2.0Hz), 5.55 (1H, dd, J=12.6, 2.2 Hz), 4.18 (1H, d, J=16.2 Hz), 4.01-3.97(1H, m), 3.91 (3H, s), 3.37 (1H, dd, J=16.4, 11.1 Hz), 2.76-2.69 (2H,m), 2.68 (1H, d, J=12.6 Hz), 2.61 (1H, d, J=16.2 Hz), 2.52-2.40 (1H, m),1.89-1.80 (2H, m).

Example 2K((4aR,8aS)-6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

Using trifluoroacetic acid/dichloromethane in place of HCl/dioxane.LCMS: RT 2.54 min, m+H=603.2; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d,J=5.1 Hz), 8.10 (1H, m), 7.70 (1H, s), 7.66-7.65 (2H, m), 7.50-7.45 (2H,m), 7.33 (1H, s), 7.18-7.12 (2H, m), 6.60 (1H, d, J=2.0 Hz), 5.48 (1H,dd, J=12.1, 2.0 Hz), 4.23 (1H, d, J=16.4 Hz), 4.18 (2H, q, J=7.2 Hz),3.85-3.83 (1H, m), 3.42 (1H, dd, J=16.4, 11.1 Hz), 2.71 (1H, dd, J=16.2,6.0 Hz), 2.60 (1H, d, J=16.2 Hz), 2.46-2.34 (1H, m), 2.29 (1H, d, J=12.1Hz), 1.82-1.71 (2H, m), 1.51 (3H, t, J=7.2 Hz).

Example 2L((4aR,8aS)-6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

Using trifluoroacetic acid/dichloromethane in place of HCl/dioxane.LCMS: RT 2.70 min, m+H=603.3; 1H NMR (400 MHz, CDCl3): δ 8.78 (1H, d,J=5.0 Hz), 8.07 (1H, m), 7.66-7.64 (1H, m), 7.49-7.44 (2H, m), 7.36 (1H,d, J=2.0 Hz), 7.29 (1H, s), 7.18-7.12 (2H, m), 6.58 (1H, d, J=2.0 Hz),5.57 (1H, dd, J=12.5, 2.0 Hz), 4.32 (3H, m), 3.98-3.94 (1H, m), 3.38(1H, dd, J=16.2, 10.8 Hz), 2.76-2.69 (2H, m), 2.66 (1H, d, J=12.6 Hz),2.61 (1H, d, J=16.2 Hz), 2.51-2.40 (1H, m), 1.89-1.80 (2H, m), 1.39 (3H,t, J=7.2 Hz).

Example 2M((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS: RT 2.79 min, m+H=590.7; 1H NMR (400 MHz, CDCl3): δ 7.94 (1H, d,J=3.1 Hz), 7.82 (2H, d, J=8.2 Hz), 7.71 (2H, d, J=8.2 Hz), 7.59 (1H, d,J=3.1 Hz), 7.48-7.42 (2H, m), 7.34 (1H, s), 7.17-7.10 (2H, m), 5.43 (1H,dd, J=12.3, 2.1 Hz), 4.16 (1H, d, J=16.0 Hz), 4.05-3.96 (1H, m), 3.37(1H, dd, J=16.0, 10.6 Hz), 2.69 (1H, dd, J=16.4, 5.7 Hz), 2.59-2.42 (4H,m), 1.84-1.77 (2H, m).

Example 2N((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.61 min, m+H=549.9; 1H NMR (400 MHz, CDCl3): δ 8.68 (1H, ddd,J=4.8, 1.7, 1.0 Hz), 7.88-7.78 (3H, m), 7.54-7.42 (3H, m), 7.37 (1H, s),7.21-7.12 (2H, m), 5.70 (1H, dd, J=12.4, 2.1 Hz), 4.90 (1H, sept, J=6.7Hz), 4.40 (1H, d, J=16.3 Hz), 4.02-3.96 (1H, m), 3.48 (1H, dd, J=16.3,10.9 Hz), 2.72 (1H, dd, J=16.3, 5.9 Hz), 2.66-2.58 (2H, m), 2.55 (1H, d,J=12.4 Hz), 2.46 (1H, qd, J=13.8, 5.0 Hz), 1.83-1.75 (2H, m), 1.62 (6H,d, J=6.7 Hz).

Example 2O((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS: RT 2.68 min, m+H=604.3; 1H NMR (400 MHz, CDCl3): δ 8.86 (1H, d,J=5.0 Hz), 8.10 (1H, m), 7.81 (1H, s), 7.67-7.66 (1H, m), 7.50-7.45 (1H,m), 7.33 (1H, s), 7.18-7.12 (2H, m), 5.64 (1H, dd, J=12.4, 2.0 Hz), 4.52(2H, q, J=7.3 Hz), 4.25 (1H, d, J=16.4 Hz), 3.98-3.93 (1H, m), 3.43 (1H,dd, J=16.4, 11.1 Hz), 2.72 (1H, dd, J=16.2, 5.9 Hz), 2.60 (1H, d, J=16.2Hz), 2.64-2.58 (2H, m), 2.56 (1H, d, J=12.6 Hz), 2.48-2.36 (1H, m),1.84-1.76 (2H, m), 1.60 (3H, t, J=7.3 Hz).

Example 2P((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS: RT 2.45 min, m+H=590.2; 1H NMR (400 MHz, CDCl3): δ 8.85 (1H, d,J=5.0 Hz), 8.11-8.10 (1H, m), 7.88 (1H, s), 7.66-7.65 (1H, m), 7.50-7.45(2H, m), 7.34 (1H, s), 7.18-7.12 (2H, m), 5.68 (1H, dd, J=12.6, 2.0 Hz),4.26 (1H, d, J=16.4 Hz), 4.15 (3H, s), 3.97-3.92 (1H, m), 3.43 (1H, dd,J=16.4, 11.1 Hz), 2.78-2.70 (3H, m), 2.63 (1H, d, J=16.2 Hz), 2.47-2.36(1H, m), 1.87-1.78 (2H, m).

Example 2Q((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.68 min, m+H=585.6; 1H NMR (400 MHz, CDCl3): δ 8.61-8.53 (1H,m), 7.96 (1H, t, J=7.7 Hz), 7.86 (1H, d, J=7.7 Hz), 7.78-7.68 (3H, m),7.46-7.39 (2H, m), 7.37 (1H, ddd, J=6.9, 4.8, 2.0 Hz), 7.31 (1H, s),7.14-7.01 (2H, m), 5.68 (1H, dd, J=12.9, 2.1 Hz), 4.32 (1H, d, J=16.3Hz), 4.05-3.94 (1H, m), 3.46-3.33 (1H, m), 2.93 (1H, td, J=12.6, 3.1Hz), 2.91 (1H, d, J=12.9 Hz), 2.65 (1H, dd, J=16.3, 6.0 Hz), 2.54 (1H,d, J=16.3 Hz), 2.37 (1H, qd, J=12.9, 5.1 Hz), 1.87-1.76 (1H, m),1.76-1.64 (1H, m).

Example 2R((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone

LCMS: RT 2.44 min, m+H=536.3; 1H NMR (400 MHz, CDCl3): δ: 8.49 (1H, d,J=5.0 Hz), 7.80 (1H, s), 7.66-7.65 (1H, m), 7.50-7.45 (2H, m), 7.32 (1H,s), 7.24-7.23 (1H, m), 7.17-7.11 (2H, m), 5.73 (1H, dd, J=12.5, 2.2 Hz),4.36 (1H, d, J=16.1 Hz), 4.25 (3H, s), 3.98-3.94 (1H, m), 3.44 (1H, dd,J=16.4, 11.3 Hz), 2.69 (1H, dd, J=16.1, 5.9 Hz), 2.64-2.42 (4H, m), 2.37(3H, s), 1.79-1.70 (2H, m).

Example 2S((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS: RT 2.50 min, m+H=556.2; 1H NMR (400 MHz, CDCl3): δ: 8.85 (1H, d,J=2.2 Hz), 8.18 (1H, d, J=2.2 Hz), 7.83 (1H, s), 7.50-7.44 (2H, m), 7.35(1H, s), 7.17-7.11 (2H, m), 5.54 (1H, dd, J=12.6, 2.0 Hz), 4.44 (2H, dd,J=7.2 Hz), 4.19 (1H, d, J=16.3 Hz), 3.99-3.95 (1H, m), 3.46 (1H, dd,J=16.4, 11.1 Hz), 2.68 (1H, dd, J=16.4, 5.9 Hz), 2.62-2.48 (4H, m), 2.02(2H, sext, J=7.2 Hz), 1.83-1.75 (2H, m), 0.94 (3H, t, J=7.2 Hz).

Example 2T3-(((4aR,8aS)-1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile

LCMS: RT 2.46 min, m+H=542.2; 1H NMR (400 MHz, CDCl3): δ: 8.63 (1H, ddd,J=4.7, 1.3 Hz), 7.92-7.88 (2H, m), 7.81-7.79 (2H, m), 7.77 (1H, ddd,J=7.7, 1.3 Hz), 7.58 (1H, dt, J=7.7, 0.6 Hz), 7.48-7.42 (3H, m), 7.30(1H, s), 7.17-7.11 (2H, m), 5.66 (1H, dd, J=12.3, 2.1 Hz), 4.27 (1H, d,J=16.1 Hz), 3.98-3.95 (1H, m), 3.39 (1H, dd, J=16.1, 11.2 Hz), 2.68 (1H,dd, J=16.3, 6.1 Hz), 2.55-2.39 (4H, m), 1.80-1.69 (2H, m).

Example 2U((4aR,8aS)-6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.79 min, m+H=603.3; 1H NMR (400 MHz, CDCl3): δ 8.63 (1H, ddd,J=4.7, 1.3 Hz), 7.79-7.78 (2H, m), 7.66 (1H, dd, J=7.7 Hz), 7.54 (1H, d,J=8.0 Hz), 7.49-7.42 (4H, m), 7.30 (1H, s), 7.17-7.11 (2H, m), 5.64 (1H,dd, J=12.4, 2.0 Hz), 4.26 (1H, d, J=16.1 Hz), 4.00-3.96 (1H, m), 3.39(1H, dd, J=16.4, 11.2 Hz), 2.69 (1H, dd, J=16.2, 6.0 Hz), 2.60-2.41 (4H,m), 1.80-1.71 (2H, m).

Example 2V((4aR,8aS)-1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.39 min, m+H=589.3; 1H NMR (400 MHz, CDCl3): δ 8.61 (1H, ddd,J=4.7, 1.6, 0.9 Hz), 8.05 (1H, d, J=2.0 Hz), 7.83-7.81 (1H, m), 7.77(1H, dd, J=7.4, 1.6 Hz), 7.49-7.44 (2H, m), 7.40 (1H, ddd, J=7.3, 4.7,1.6 Hz), 7.32 (1H, s), 7.16-7.10 (2H, m), 7.04 (1H, d, J=2.0 Hz), 5.51(1H, dd, J=12.1, 2.0 Hz), 4.31 (1H, d, J=16.2 Hz), 4.23-4.21 (2H, m),3.87-3.84 (1H, m), 3.55-3.53 (2H, m), 3.43 (1H, dd, J=16.4, 11.1 Hz),3.22 (3H, s), 2.67 (1H, dd, J=16.3, 6.1 Hz), 2.54 (1H, d, J=16.2 Hz),2.47-2.36 (2H, m), 2.32 (1H, J=12.0 Hz), 1.76-1.66 (2H, m).

Example 2W((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS: RT 2.48 min, m+H=556.2; 1H NMR (400 MHz, CDCl3): δ 7.94 (1H, d,J=3.1 Hz), 7.87 (1H, s), 7.62 (1H, d, J=3.1 Hz), 7.48-7.42 (2H, m), 7.32(1H, s), 7.17-7.11 (2H, m), 5.45 (1H, dd, J=12.7, 2.1 Hz), 4.38-4.27(2H, m), 4.14 (1H, d, J=16.1 Hz), 4.06-4.01 (1H, m), 3.37 (1H, dd,J=16.1, 11.1 Hz), 2.86-2.70 (3H, m), 2.61 (1H, d, J=16.1 Hz), 2.53-2.42(1H, m), 1.97-1.82 (4H, m), 0.94 (3H, t, J=7.3 Hz).

Example 2X((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS: RT 2.56 min, m+H=590.3; 1H NMR (400 MHz, CDCl3): δ 8.77 (1H, d,J=5.0 Hz), 8.04 (1H, m), 7.89 (1H, s), 7.69-7.67 (1H, m), 7.48-7.43 (2H,m), 7.28 (1H, s), 7.18-7.12 (2H, m), 5.59 (1H, dd, J=12.6, 2.0 Hz), 4.12(1H, d, J=16.3 Hz), 4.06 (3H, s), 4.06-4.01 (1H, m), 3.35 (1H, dd,J=16.4, 11.2 Hz), 2.82-2.72 (3H, m), 2.61 (1H, d, J=16.2 Hz), 2.47-2.36(1H, qd, J=13.0, 5.2 Hz), 1.91-1.82 (2H, m).

Example 2Y((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS: RT 2.30 min, m+H=528.2; 1H NMR (400 MHz, CDCl3): δ 8.02 (1H, d,J=3.1 Hz), 7.82 (1H, s), 7.61 (1H, d, J=3.1 Hz), 7.49-7.44 (2H, m), 7.35(1H, s), 7.17-7.10 (2H, m), 5.58 (1H, dd, J=12.6, 2.1 Hz), 4.26 (3H, s),4.22 (1H, d, J=16.4 Hz), 4.04-3.96 (1H, m), 3.41 (1H, dd, J=16.4, 11.4Hz), 2.73-2.58 (4H, m), 2.54-2.43 (1H, m), 1.88-1.77 (2H, m).

Example 2Z((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS: RT 2.53 min, m+H=556.2; 1H NMR (400 MHz, CDCl3): δ 8.03 (1H, d,J=3.1 Hz), 7.80 (1H, s), 7.61 (1H, d, J=3.1 Hz), 7.49-7.44 (2H, m), 7.35(1H, s), 7.17-7.11 (2H, m), 5.60 (1H, dd, J=12.6, 2.1 Hz), 4.88 (1H,sept, J=6.7 Hz), 4.23 (1H, d, J=16.4 Hz), 4.02-3.98 (1H, m), 3.41 (1H,dd, J=16.1, 11.2 Hz), 2.73-2.58 (4H, m), 2.49 (1H, dq, J=12.5, 5.0 Hz),1.88-1.74 (2H, m), 1.61 (6H, d, J=6.7 Hz).

Example 2AA((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.41 min, m+H=549.3; 1H NMR (400 MHz, CDCl3): 8.63 (1H, ddd,J=4.7, 1.6, 0.8 Hz), 7.82 (1H, ddd, J=7.8, 1.3, 0.8 Hz), 7.77 (1H, dd,J=7.4, 1.6 Hz), 7.72 (1H, s), 7.64 (1H, d, J=0.8 Hz), 7.49-7.44 (2H, m),7.41 (1H, ddd, J=7.3, 4.8, 1.6 Hz), 7.31 (1H, s), 7.15-7.09 (2H, m),5.51 (1H, dd, J=12.0, 2.0 Hz), 4.47 (1H, sept, J=6.7 Hz), 4.34 (1H, d,J=16.1 Hz), 3.85-3.78 (1H, m), 3.43 (1H, dd, J=16.4, 11.2 Hz), 2.68 (1H,dd, J=16.2, 6.0 Hz), 2.56 (1H, d, J=16.2 Hz), 2.46-2.32 (2H, m), 2.26(1H, d, J=12.0 Hz), 1.82-1.64 (2H, m), 1.49 (6H, dd, J=6.7, 1.1 Hz).

Example 2AB((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.43 min, m+H=536.2; 1H NMR (400 MHz, CDCl3): 8.63 (1H, ddd,J=4.7, 1.6, 0.9 Hz), 7.84-7.77 (3H, m), 7.50-7.45 (2H, m), 7.43 (1H,ddd, J=7.0, 4.7, 1.6 Hz), 7.33 (1H, s), 7.17-7.11 (2H, m), 5.68 (1H, dd,J=12.4, 1.9 Hz), 4.51 (2H, q, J=7.3 Hz), 4.36 (1H, d, J=16.2 Hz),3.99-3.92 (1H, m), 3.45 (1H, dd, J=16.2, 11.3 Hz), 2.69 (1H, dd, J=16.2,6.0 Hz), 2.63-2.55 (2H, m), 2.52 (1H, d, J=12.3 Hz), 2.43 (1H, dq,J=13.4, 4.8 Hz), 1.80-1.71 (2H, m), 1.59 (3H, t, J=7.3 Hz).

Example 2AC((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.31 min, m+H=522.2; 1H NMR (400 MHz, CDCl3): δ 8.65 (1H, ddd,J=4.7, 1.6, 0.9 Hz), 7.84-7.77 (3H, m), 7.50-7.46 (2H, m), 7.43 (1H,ddd, J=7.1, 4.7, 1.6 Hz), 7.33 (1H, s), 7.17-7.11 (2H, m), 5.68 (1H, dd,J=12.4, 2.0 Hz), 4.36 (1H, d, J=16.2 Hz), 3.99-3.91 (1H, m), 4.25 (3H,s), 3.45 (1H, dd, J=16.2, 11.3 Hz), 2.70 (1H, dd, J=16.2, 6.0 Hz),2.64-2.55 (2H, m), 2.53 (1H, d, J=12.4 Hz), 2.43 (1H, dq, J=13.4, 4.7Hz), 1.80-1.71 (2H, m).

Example 2AD((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS: RT 2.79 min, m+H=618.3; 1H NMR (400 MHz, CDCl3): δ 8.87 (1H, d,J=5.0 Hz), 8.10-8.09 (1H, m), 7.80 (1H, s), 7.66 (1H, dd, J=5.0, 1.0Hz), 7.50-7.44 (2H, m), 7.32 (1H, s), 7.17-7.11 (2H, m), 5.64 (1H, dd,J=12.5, 2.0 Hz), 4.88 (1H, sept, J=6.6 Hz), 4.25 (1H, d, J=16.2 Hz),3.99-3.91 (1H, m), 3.43 (1H, dd, J=16.2, 10.9 Hz), 2.71 (1H, dd, J=16.4,6.0 Hz), 2.63-2.56 (2H, m), 2.54 (1H, d, J=12.4 Hz), 2.42 (1H, dq,J=13.4, 4.8 Hz), 1.86-1.75 (2H, m), 1.60 (6H, d, J=6.6 Hz).

Example 2AE((4aR,8aS)-6-((2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone

LCMS: RT 2.39 min, m+H=576.2; 1H NMR (400 MHz, CDCl3): δ 8.87 (1H, d,J=5.0 Hz), 8.11-8.10 (1H, m), 7.93 (1H, s), 7.66 (1H, dd, J=5.0, 1.0Hz), 7.50-7.45 (2H, m), 7.39 (1H, s), 7.19-7.13 (2H, m), 5.64 (1H, dd,J=12.5, 1.9 Hz), 4.27 (1H, d, J=16.2 Hz), 3.98-3.91 (1H, m), 3.42 (1H,dd, J=16.2, 11.3 Hz), 2.71 (1H, dd, J=16.6, 6.1 Hz), 2.66-2.59 (3H, m),2.40 (1H, dq, J=13.5, 4.7 Hz), 1.85-1.74 (2H, m).

Example 2AF((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone

LCMS: RT 2.37 min, m+H=550.2; 1H NMR (400 MHz, CDCl3): 8.65 (1H, ddd,J=4.7, 1.6, 0.9 Hz), 7.90 (1H, s), 7.84 (1H, ddd, J=8.0, 1.3, 0.9 Hz),7.79 (1H, dt, J=7.3, 1.6 Hz), 7.51-7.46 (2H, m), 7.42 (1H, ddd, J=7.3,4.7, 1.6 Hz), 7.34 (1H, s), 7.17-7.11 (2H, m), 5.70 (1H, dd, J=12.4, 2.0Hz), 4.85 (1H, sept, J=6.7 Hz), 4.38 (1H, d, J=16.2 Hz), 4.01-3.92 (1H,m), 3.45 (1H, dd, J=16.4, 11.0 Hz), 2.81-2.68 (3H, m), 2.59 (1H, d,J=15.9 Hz), 2.43 (1H, dq, J=13.9, 5.0 Hz), 1.84-1.73 (2H, m), 1.59 (6H,dd, J=6.7, 2.0 Hz).

Example 2AG((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone

LCMS: RT 2.58 min, m+H=592.2; 1H NMR (400 MHz, CDCl3): 1H NMR (400 MHz,CDCl3) δ 8.07-8.01 (2H, m), 7.95 (1H, d, J=7.8 Hz), 7.83 (1H, d, J=7.8Hz), 7.60 (1H, d, J=3.1 Hz), 7.48-7.45 (2H, m), 7.34 (1H, s), 7.16-7.12(2H, m), 5.62 (1H, dd, J=12.9, 1.6 Hz), 4.24 (1H, d, J=16.1 Hz),4.13-4.09 (1H, m), 3.42 (1H, dd, J=16.1, 11.6 Hz), 3.07-3.00 (2H, m),2.72 (1H, dd, J=16.4, 6.1 Hz), 2.63 (1H, d, J=16.2 Hz), 2.50 (1H, dq,J=12.9, 5.0 Hz), 1.99-1.90 (1H, m), 1.81-1.78 (1H, m).

Example 2AH((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS: RT 2.53 min, m+H=592.2; 1H NMR (400 MHz, CDCl3): 1H NMR (400 MHz,CDCl3) δ 8.83 (1H, d, J=2.1 Hz), 8.15 (1H, d, J=2.1 Hz), 8.07-8.03 (1H,m), 7.96 (1H, d, J=7.6 Hz), 7.82 (1H, dd, J=7.6, 0.9 Hz), 7.50-7.45 (2H,m), 7.33 (1H, s), 7.17-7.11 (2H, m), 5.58 (1H, dd, J=12.9, 2.0 Hz), 4.18(1H, d, J=16.4 Hz), 4.10-4.06 (1H, m), 3.47 (1H, dd, J=16.2, 11.3 Hz),3.04-2.97 (1H, m), 2.95 (1H, d, J=13.1 Hz), 2.70 (1H, dd, J=16.2, 6.1Hz), 2.59-2.45 (2H, m), 1.95-1.97 (1H, m), 1.82-1.73 (1H, m).

Example 2AI((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS: RT 2.21 min, m+H=528.2; 1H NMR (400 MHz, CDCl3): 1H NMR (400 MHz,CDCl3) δ 8.85 (1H, d, J=2.0 Hz), 8.17 (1H, d, J=2.0 Hz), 7.82 (1H, s),7.50-7.45 (2H, m), 7.34 (1H, s), 7.17-7.11 (2H, m), 5.53 (1H, dd,J=12.6, 2.1 Hz), 4.26 (3H, s), 4.19 (1H, d, J=16.4 Hz), 4.00-3.96 (1H,m), 3.46 (1H, dd, J=15.7, 10.9 Hz), 2.72-2.43 (5H, m), 1.84-1.73 (2H,m).

Example 2AJ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS: RT 2.46 min, m+H=556.2; 1H NMR (400 MHz, CDCl3): 1H NMR (400 MHz,CDCl3) δ 8.86 (1H, d, J=2.1 Hz), 8.17 (1H, d, J=2.1 Hz), 7.80 (1H, s),7.50-7.45 (2H, m), 7.35 (1H, s), 7.17-7.11 (2H, m), 5.54 (1H, dd,J=12.6, 2.1 Hz), 4.89 (1H, sept, J=6.8 Hz), 4.19 (1H, d, J=16.4 Hz),4.02-3.94 (1H, m), 3.46 (1H, dd, J=16.4, 12.0 Hz), 2.71-2.43 (5H, m),1.84-1.72 (2H, m), 1.61 (6H, d, J=6.8 Hz).

Example 2AK((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone

LCMS: RT 2.33 min, m+H=542.2; 1H NMR (400 MHz, CDCl3): 1H NMR (400 MHz,CDCl3) δ 8.87 (1H, d, J=2.0 Hz), 8.19 (1H, d, J=2.0 Hz), 7.83 (1H, s),7.52-7.46 (2H, m), 7.36 (1H, s), 7.19-7.13 (2H, m), 5.55 (1H, dd,J=12.6, 2.2 Hz), 4.54 (2H, q, J=7.2 Hz), 4.20 (1H, d, J=16.4 Hz),4.01-3.97 (1H, m), 3.48 (1H, dd, J=15.8, 11.0 Hz), 2.73-2.46 (5H, m),1.87-1.77 (2H, m), 1.62 (3H, t, J=7.2 Hz).

Example 3 Human Glucocorticoid Receptor (GR) Fluorescence Polarisation(FP) Binding Assay

The following is a description of a FP assay for measuring compoundinhibition of labelled glucocorticoid binding to the human recombinantGR.

The binding affinity of test compounds was determined using a FP bindingassay using human recombinant GR (PanVera P2812) and a fluorescentlabelled glucocorticoid ligand (Fluorome GS Red) (PanVera P2894). Thepresence of inhibitors prevents the formation of a GS Red/GR complexresulting in a decrease in the measured polarisation value. The changein polarisation value in the presence of test compounds is used tocalculate the binding affinity of the compound for GR.

This assay was performed in 384 well, black, round-bottom, polypropylenemicro titre plates in a final volume of 20 μl. The assay contained 5 μl1 nM GR (final concentration), 5 μl 0.5 nM Fluorome GS Red (finalconcentration) in the presence of 10 μl test compounds. Positive controlwells (high polarisation) receive, 10 μl 2% (v:v) DMSO vehicle (1% (v/v)final concentration)+5 μl 1 nM GR and 5 μl 0.5 nM Fluorome GS Red.Negative control wells (low polarisation) receive 10 μl 2 μMdexamethasone (1 μM final concentration)+5 μl 1 nM GR and 5 μl 0.5 nMFluorome GS Red. Assay blank background wells (used for normalisation)receive 15 μl 1×GS screening buffer+5 μl GR.

For the IC₅₀ determination (concentration of compound that displaces 50%of the bound GS Red), compounds were tested at eight differentconcentrations in duplicate in two independently performed experiments.Compounds were prepared as solubilised solids at 10 mM in DMSO. On theday of assay, an 8 point half-log serial dilution (55 μl DMSO+25 μlcompound solution) was prepared. A 1:50 dilution (1 μl compoundsolution+49 μl 1×GR screening buffer) was prepared for each compound.The compounds were prepared at 2× final assay concentration.

The reagents were added to the 384 well micro titre plates in thefollowing order: 10 μl test compound/vehicle/1 μM dexamethasone, 5 μlFluorome GS Red and 5 μl GR. The plates were mixed and incubated for 4hour at room temperature. FP was measured using an Envision Excite platereader with 535 nm excitation and 590 nm emission interference filters.

Milli-polarisation (mP) values were calculated using the below equation:

mP=1000*(S−G*P)/(S+G*P)

where S and P are assay blank background subtracted fluorescence units,G=G-factor (1.07).

Compound IC₅₀ values were calculated by plotting a [compound] v. %inhibition curve and fitting the data to a 4-parameter logistic fitequation. Compound K_(i) (equilibrium dissociation constant) values weredetermined from the experimental IC₅₀ values using a ligand depletioncorrection equation (see below) assuming the antagonists werecompetitive inhibitors with respect to dexamethasone (PharmacologicAnalysis of Drug Receptor Interactions, 2^(nd) Ed., p 385-410, 1993,Raven Press, New York).

$K_{i} = \frac{\left( L_{b} \right)*\left( {IC}_{50} \right)*\left( K_{d} \right)}{{\left( L_{o} \right)*\left( R_{o} \right)} + {L_{b}*\left( {R_{o} - L_{o} + L_{b} - k_{d}} \right)}}$

Equilibrium dissociation constant of GS red ligand (K_(d)) 0.3 nM Boundtracer concentration (L_(b)) 0.3 nM Total tracer concentration (L_(o))0.5 nM Total receptor concentration (R_(o)) 1.0 nM

Reagents:

10×GR screening buffer (100 mM potassium phosphate pH 7.4, 200 mMNa₂MoO₄, 1 mM EDTA, 20% (v/v) DMSO). To prepare 1×GR screening buffer,combine 1 ml 10×GR screening buffer (PanVera P2814)+1 ml stabilisingpeptide (PanVera P2815)+7.95 ml 4° C. MQ water. Add 50 μl 1M DTT, vortexand place on ice until use.

Example 4 HepG2 Tyrosine Aminotransferase (TAT) Assay

Glucocorticoid mediated activation of TAT occurs by transactivation ofglucocorticoid response elements in the TAT promoter by glucocorticoidreceptor-agonist complex. The following protocol describes an assay formeasuring induction of TAT by dexamethasone in HepG2 cells (a humanliver hepatocellular carcinoma cell line; ECACC, UK).

TAT activity was measured as outlined in the literature by A. Ali etal., J. Med. Chem., 2004, 47, 2441-2452. Dexamethasone induced TATproduction with an average EC₅₀ value (half-maximal effect) of 20 nM.

HepG2 cells were cultured using MEME media supplemented with 10% (v/v)foetal bovine serum; 2 mM L-glutamine and 1% (v/v) NEAA at 37° C.,5%/95% (v/v) CO₂/air. The HepG2 cells were counted and adjusted to yielda density of 0.125×10⁶ cells/ml in RPMI 1640 without phenol red, 10%(v/v) charcoal stripped FBS, 2 mM L-glutamine and seeded at 25,000cells/well in 200 μl into 96 well, sterile, tissue culture micro titreplates, and incubated at 37° C., 5% CO₂ for 24 hours

Growth media was removed and replaced with assay media {RPMI 1640without phenol red, 2 mM L-glutamine+10 μM forskolin}. Test compoundswere screened against a challenge of 100 nM dexamethasone. Compoundswere serially half log diluted in 100% (v/v) dimethylsulphoxide from a10 mM stock. Then an 8-point half-log dilution curve was generatedfollowed by a 1:100 dilution into assay media to give a 10× final assay[compound]: this resulted in final assay [compound] that ranged 10 to0.003 μM in 0.1% (v/v) dimethylsulfoxide.

Test compounds were pre-incubated with cells in micro-titre plates for30 minutes at 37° C., 5/95 (v/v) CO₂/air, before the addition of 100 nMdexamethasone and then subsequently for 20 hours to allow optimal TATinduction.

HepG2 cells were then lysed with 30 μl of cell lysis buffer containing aprotease inhibitor cocktail for 15 minutes at 4° C. 155 μl of substratemixture was then added containing 5.4 mM Tyrosine sodium salt, 10.8 mMalpha ketoglutarate and 0.06 mM pyridoxal 5′ phosphate in 0.1M potassiumphosphate buffer (pH 7.4). After 2 hours incubation at 37° C. thereaction was terminated by the addition of 15 μl of 10M aqueouspotassium hydroxide solution, and the plates incubated for a further 30minutes at 37° C. The TAT activity product was measured by absorbance atλ 340 nm.

IC₅₀ values were calculated by plotting % inhibition (normalised to 100nM dexamethasone TAT stimulation) v. [compound] and fitting the data toa 4 parameter logistic equation. IC₅₀ values were converted to Ki(equilibrium dissociation constant) using the Cheng and Prusoffequation, assuming the antagonists were competitive inhibitors withrespect to dexamethasone.

TABLE 1 Activity Data

GR binding TAT Example R¹ R^(1a) Ring J R² (nM) (nM) 1A pyridin-2-yl Hphenyl 4-CF₃ ++ ++ 1B pyridin-2-yl H phenyl 3,4-Cl + ++ 1C pyridin-2-ylH phenyl 3,4-F + ++ 2A pyridin-2-yl H 1,2,3-triazol-4-yl 2-nPr +++ +++2B pyridin-2-yl H pyrazol-4-yl 1-nPr +++ +++ 2C pyridin-2-yl 4-CF₃1,2,3-triazol-4-yl 2-Me ++ +++ 2D pyridin-2-yl 4-CF₃ pyrazol-4-yl 1-nPr+++ +++ 2E thiazol-2-yl H pyrazol-4-yl 1-nPr +++ +++ 2F pyridin-2-yl Hphenyl 3-F + ++ 2G pyridin-2-yl H phenyl 3-CF₃ + ++ 2H pyridin-2-yl4-CF₃ pyrazol-4-yl 1-Me + ++ 2I pyridin-2-yl 4-CF₃ pyrazol-3-yl 1-Me ++++ 2J pyridin-2-yl 4-CF₃ pyrazol-5-yl 1-Me + ++ 2K pyridin-2-yl 4-CF₃pyrazol-4-yl 1-Et ++ ++ 2L pyridin-2-yl 4-CF₃ pyrazol-5-yl 2-Et + ++ 2Mthiazol-2-yl H phenyl 4-CF₃ + ++ 2N pyridin-2-yl H 1,2,3-triazol-4-yl2-iPr +++ +++ 2O pyridin-2-yl 4-CF₃ 1,2,3-triazol-4-yl 2-Et ++ +++ 2Ppyridin-2-yl 4-CF₃ 1,2,3-triazol-4-yl 1-Me + ++ 2Q pyridin-2-yl Hpyridin-2-yl 6-CF₃ ++ +++ 2R pyridin-2-yl 4-Me 1,2,3-triazol-4-yl 2-Me+++ +++ 2S thiazol-4-yl H 1,2,3-triazol-4-yl 2-nPr +++ ++ 2Tpyridin-2-yl H phenyl 3-CN + ++ 2U pyridin-2-yl H phenyl 3-F, 4-CF₃ + ++2V pyridin-2-yl H 4-methyl-3,4-dihydro-2H- + ++pyrido[3,2-b][1,4]oxazin- 7-yl 2W thiazol-2-yl H 1,2,3-triazol-5-yl1-nPr + + 2X pyridin-2-yl 4-CF₃ 1,2,3-triazol-5-yl 1-Me + + 2Ythiazol-2-yl H 1,2,3-triazol-4-yl 2-Me + + 2Z thiazol-2-yl H1,2,3-triazol-4-yl 2-iPr +++ ++ 2AA pyridin-2-yl H pyrazol-4-yl 1-iPr+++ ++ 2AB pyridin-2-yl H 1,2,3-triazol-4-yl 2-Et +++ ++ 2ACpyridin-2-yl H 1,2,3-triazol-4-yl 2-Me + ++ 2AD pyridin-2-yl 4-CF₃1,2,3-triazol-4-yl 2-iPr +++ +++ 2AE pyridin-2-yl 4-CF₃1,2,3-triazol-4-yl H + + 2AF pyridin-2-yl H 1,2,3-triazol-4-yl 1-iPr +++ 2AG thiazol-2-yl H pyridin-2-yl 6-CF₃ ++ ++ 2AH thiazol-4-yl Hpyridin-2-yl 6-CF₃ ++ +++ 2AI thiazol-4-yl H 1,2,3-triazol-4-yl 2-Me +++ 2AJ thiazol-4-yl H 1,2,3-triazol-4-yl 2-iPr +++ +++ 2AK thiazol-4-ylH 1,2,3-triazol-4-yl 2-Et +++In Table 1, GR Binding compounds with a K_(i) value of less than 0.5 nMare designated with +++; compounds with a K_(i) value from 0.5 nM toless than 1.0 nM are designated with ++; and compounds with a K_(i)value of at least 1.0 nM are designated with +. TAT activity with aK_(i) value of less than 20 nM are designated with +++, compounds with aK_(i) value from 20 nM to less than 100 nM are designated with ++; andcompounds with a K_(i) value of at least 100 nM are designated with +.

Although the foregoing invention has been described in some detail byway of illustration and Example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

What is claimed is:
 1. A compound having the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, —CN, —OH, —NR^(2a)R^(2b), —C(O)R^(2a), —C(O)OR^(2a),—C(O)NR^(2a)R^(2b), —SR^(2a), —S(O)R^(2a), —S(O)₂R^(2a), C₃₋₈cycloalkyl, and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatomseach independently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(ea) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; subscript n is an integerfrom 0 to 3; or salts and isomers thereof.
 2. The compound of claim 1,wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O, and S, optionally substituted with 1-3 groups eachindependently selected from R^(1a); each R^(1a) is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and C₃₋₈ cycloalkyl; ringJ is selected from the group consisting of an aryl ring and a heteroarylring having from 5 to 6 ring members and from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O, and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, CN, —NR^(2a)R^(2b), C₃₋₈ cycloalkyl, andC₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms each independentlyselected from the group consisting of N, O and S; alternatively, two R²groups on adjacent ring atoms are combined to form a heterocycloalkylring having from 5 to 6 ring members and from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S, whereinthe heterocycloalkyl ring is optionally substituted with from 1 to 3R^(2c) groups; R^(2a), R^(2b) and R^(2c) are each independently selectedfrom the group consisting of hydrogen and C₁₋₆ alkyl; each R^(3a) isindependently halogen; and subscript n is an integer from 0 to
 3. 3. Thecompound of any of claims 1 to 2, wherein R¹ is a heteroaryl ring havingfrom 5 to 6 ring members and from 1 to 3 heteroatoms each independentlyselected from the group consisting of N, O, and S, optionallysubstituted with 1-2 groups each independently selected from R^(1a);each R^(1a) is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, and C₁₋₆ haloalkyl; ring J is selectedfrom the group consisting of an aryl ring and a heteroaryl ring havingfrom 5 to 6 ring members and from 1 to 3 heteroatoms each independentlyselected from the group consisting of N and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen,C₁₋₆ haloalkyl and —CN; R^(3a) is F; and subscript n is an integer from0 to
 1. 4. The compound of any of claims 1 to 3, wherein R¹ is aheteroaryl ring having from 5 to 6 ring members and from 1 to 2heteroatoms each independently selected from the group consisting of Nand S, optionally substituted with 1-2 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; ring J isselected from the group consisting of phenyl, pyridine, pyrazole, andtriazole; each R² is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl and —CN; and R^(3a) is F.5. The compound of any of claims 1 to 4, wherein R¹ is selected from thegroup consisting of pyridine and thiazole; ring J is selected from thegroup consisting of phenyl, pyridine, pyrazole, and triazole; each R² isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl and —CN; and R^(3a) is F.
 6. The compoundof any of claims 1 to 5, wherein R¹ is selected from the groupconsisting of 2-thiazole, 4-thiazole, 5-thiazole, 2-pyridine,3-pyridine, and 4-pyridine.
 7. The compound of any of claims 1 to 6,wherein R¹ is selected from the group consisting of 2-thiazole,4-thiazole and 2-pyridine.
 8. The compound of any of claims 1 to 5,wherein R¹ is pyridine.
 9. The compound of any of claims 1 to 5, whereinR¹ is thiazole.
 10. The compound of any of claims 1 to 9, wherein R^(1a)is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, and C₁₋₆ haloalkyl.
 11. The compound of any of claims 1 to 10,wherein R^(1a) is independently selected from the group consisting ofhydrogen, methyl, and trifluoromethyl.
 12. The compound of any of claims1 to 11, wherein ring J is selected from the group consisting of phenyl,pyridine, pyrazole, and triazole.
 13. The compound of any of claims 1 to12, wherein ring J is selected from the group consisting of phenyl,2-pyridine, 3-pyridine, 4-pyridine, 1-pyrazole, 3-pyrazole, 4-pyrazole,5-pyrazole, 1,2,3-triazol-4-yl, 1,2,3,-triazol-5-yl, 1,2,4-triazol-3-yl,and 1,2,4-triazol-5-yl.
 14. The compound of any of claims 1 to 13,wherein R² is independently selected from the group consisting ofhydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, —CF₃ and —CN. 15.The compound of any of claims 1 to 13, having the structure:


16. The compound of claim 1, wherein the compound is selected from thegroup consisting of:((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-6-((3,4-dichlorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-6-((3,4-difluorophenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((3-fluorophenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-6-((1-ethyl-1H-pyrazol-5-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-methylpyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-propyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,3-(((4aR,8aS)-1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8,8a,9-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-6(4H)-yl)sulfonyl)benzonitrile,((4aR,8aS)-6-((3-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-propyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-methyl-1H-1,2,3-triazol-5-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-6-((2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((1-isopropyl-1H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-101yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((6-(trifluoromethyl)pyridin-2-yl)sulfonyl)-((4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone,and((4aR,8aS)-6-((2-ethyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone.17. A pharmaceutical composition comprising a compound of any of claims1 to 16 and a pharmaceutically acceptable excipient.
 18. A method ofmodulating a glucocorticoid receptor, comprising contacting aglucocorticoid receptor with a compound of any of claims 1 to 16,thereby modulating the glucocorticoid receptor.
 19. A method of treatinga disorder through antagonizing a glucocorticoid receptor, the methodcomprising administering to a subject in need thereof, a therapeuticallyeffective amount of a compound of any of claims 1 to 16, therebytreating the disorder.